@article {pmid42841964,
year = {2026},
author = {Jellinger, KA},
title = {Depression and anxiety in vascular dementia: an update.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42841964},
issn = {1435-1463},
abstract = {Depression with a prevalence between 20% and 86% and anxiety with a prevalence up to 72% most frequently coexist with vascular dementia (VaD) and reciprocally increase disease risks. Both psychopathological disorders are usually more frequent and more severe in patients with VaD than in those with Alzheimer disease (AD). Although there is a significant association between depression and all-cause dementia, VaD with depression has more comorbidities and higher mortality than without depression. A history of depression prior to dementia is more common than in AD, while its pre-disease state is a matter of discussion. Although the diagnosis of depression related to cerebrovascular disorders is based on the criteria of DSM-V, VaD/depression has been suggested to be a distinct subtype differing from late-life depression and major depressive disorder, whereas others reported broadly similar depressive symptom profiles across VaD, AD, and AD plus VaD. Depression in the course of VaD, which is frequently underdiagnosed and undertreated, has been related to a variety of pathogenic mechanisms, in particular cerebral small vessel disease (CSVD), cerebral white matter lesions, damage to fronto-subcortical brain circuits, neuroinflammation, impaired neurotrophic support, and imbalance of neurotransmitter/kynurenine pathways. Multimarkers, like high CSVD and white matter hyperintensity burden, the presence of visible perivascular spaces, inflammatory markers, neurofilament light chain levels, and other biomarkers may support clinical diagnosis of VaD/depression. Treatment planning should consider a modest response to antidepressants, while treatment of vascular and metabolic comorbidities may provide promising targets for its prevention and treatment. Electroconvulsive therapy and transcranial direct current stimulation as augmentation treatment of an adequate pharmacotherapy are potential strategies in the management of VaD/depression that is known to be often unresponsive to antidepressants only. However, their effectiveness needs further investigation to assess which interventions are appropriate and effective in clinical practice.},
}

@article {pmid42841989,
year = {2026},
author = {Kim, H and Hwang, E and Kim, SJ},
title = {The calcium channel blocker diltiazem ameliorates parthanatos in juvenile neuronal ceroid lipofuscinosis.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {},
pmid = {42841989},
issn = {1432-1440},
support = {2021R1F1A1049562//Ministry of Education/ ; 2021374C10-2123-BD02//Korea Forestry Promotion Institute/ ; },
mesh = {*Diltiazem/pharmacology/therapeutic use ; *Neuronal Ceroid-Lipofuscinoses/drug therapy/metabolism/pathology/genetics ; Humans ; *Calcium Channel Blockers/pharmacology/therapeutic use ; *Parthanatos/drug effects ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly Adenosine Diphosphate Ribose/metabolism ; Calcium/metabolism ; },
abstract = {Accumulation of pre-mutagenic 8-oxoguanine and impaired DNA repair can lead to poly(ADP-ribose) (PAR) accumulation and parthanatos in Alzheimer's disease, the leading cause of age-dependent dementia. However, the occurrence of parthanatos has not been well established in other types of dementia, including juvenile neuronal ceroid lipofuscinosis (JNCL), a major form of juvenile dementia. In this study, we investigated parthanatos-associated pathology in JNCL using patient-derived lymphoblasts (PDLs). Quantitative immunofluorescence microscopy revealed increased accumulation of 8-oxoguanine and PAR in JNCL-PDLs. JNCL is known to exhibit elevated intracellular calcium, which activates PAR polymerase - 1 (PARP1). The L-type calcium channel blocker diltiazem effectively suppressed PAR accumulation in JNCL-PDLs, even under co-treatment with a calcium ionophore. Diltiazem also reduced 8-oxoG accumulation in JNCL-PDLs, although this effect was largely calcium independent. Subcellular fractionation followed by immunoblotting showed that diltiazem enhanced nuclear recruitment of OGG1 and its partner proteins. These protective effects were abolished by OGG1 knockdown, suggesting a dual role of diltiazem in regulating both calcium signaling and OGG1 activity. Collectively, our data identify that parthanatos as novel therapeutic target for JNCL and propose diltiazem as a potential therapeutic agent. KEY MESSAGES: Increased poly(ADP-ribose) accumulation represents a novel therapeutic target in juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations. Increased PARP1 expression and decreased PARP1 cleavage lead to elevated poly(ADP-ribose) accumulation in juvenile neuronal ceroid lipofuscinosis. Diltiazem ameliorates poly(ADP-ribose) accumulation in patient-derived cell models of juvenile neuronal ceroid lipofuscinosis by suppressing PARP1 expression and 8-oxoguanine accumulation.},
}

*Diltiazem/pharmacology/therapeutic use
*Neuronal Ceroid-Lipofuscinoses/drug therapy/metabolism/pathology/genetics
Humans
*Calcium Channel Blockers/pharmacology/therapeutic use
*Parthanatos/drug effects
Poly (ADP-Ribose) Polymerase-1/metabolism
Poly Adenosine Diphosphate Ribose/metabolism
Calcium/metabolism

@article {pmid42842169,
year = {2026},
author = {Singh, RK and Banerjee, C and Mehan, S},
title = {Beyond Histamine Blockade: Clemastine Fumarate as a Promoter of Myelin Regeneration, Inflammatory Regulation, and Neuroimmune Modulation in CNS Disorders.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42842169},
issn = {1557-1904},
mesh = {Animals ; Humans ; *Clemastine/pharmacology/therapeutic use ; *Central Nervous System Diseases/drug therapy/immunology/metabolism ; *Myelin Sheath/drug effects ; *Neuroimmunomodulation/drug effects/physiology ; *Remyelination/drug effects/physiology ; Neuroinflammatory Diseases/drug therapy/immunology ; *Histamine H1 Antagonists/pharmacology/therapeutic use ; },
abstract = {Clemastine fumarate, a first-generation H1 antihistamine, has emerged as a promising candidate for drug repurposing in neurodegenerative and neuropsychiatric disorders owing to its ability to cross the blood-brain barrier and interact with multiple central nervous system targets. Experimental studies indicate that clemastine promotes remyelination by stimulating the differentiation of oligodendrocyte precursor cells into mature, myelin-producing oligodendrocytes, thereby restoring myelin integrity and improving axonal function in experimental models. In addition to its remyelinating properties, preclinical evidence suggests that clemastine may attenuate neuroinflammation by modulating microglial activation and suppressing pro-inflammatory signalling pathways. These effects have been associated with improved structural and functional outcomes in experimental models of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, stroke, and several neuropsychiatric disorders. Mechanistically, clemastine primarily acts through muscarinic M1 receptor antagonism to promotes remyelination, while additional pathways including PI3K/Akt, ERK1/2, autophagy-related signalling, inflammasome modulation, and sigma-1 receptor signalling have been proposed based on experimental evidence but remain incompletely understood and require further mechanistic validation. Among the neurological disorders investigated multiple sclerosis currently has the strongest clinical evidence with early clinical trials demonstrating modest remyelinating activity. In contrast, evidence supporting the use of clemastine in other neurological disorders remains largely confined to preclinical studies. Several translational challenges also remain unresolved including dose optimisation, treatment timing, long-term safety, sedative and anticholinergic adverse effects, and patient selection. Future research should focus on refining pharmacokinetic properties, optimising dosing strategies, evaluating rational combination therapies, and identifying predictive biomarkers to facilitate clinical translation. Although current evidence highlights the therapeutic potential of clemastine fumarate, its application beyond multiple sclerosis remains investigational and will require rigorous mechanistic studies together with well-designed clinical trials before broader clinical use can be established.},
}

Animals
Humans
*Clemastine/pharmacology/therapeutic use
*Central Nervous System Diseases/drug therapy/immunology/metabolism
*Myelin Sheath/drug effects
*Neuroimmunomodulation/drug effects/physiology
*Remyelination/drug effects/physiology
Neuroinflammatory Diseases/drug therapy/immunology
*Histamine H1 Antagonists/pharmacology/therapeutic use

@article {pmid42842469,
year = {2026},
author = {Mah, E and Gallagher, D and Kang, Y and Gao, F and Ramirez, J and Ismail, Z and Black, SE and Cao, X and Herrmann, N and Marzolini, S and Oh, P and Chen, JJ and Survilla, K and Swardfager, W and Vieira, D and Rapoport, MJ and Lanctôt, KL},
title = {White matter hyperintensities moderate neuropsychiatric response to N-acetylcysteine and exercise therapy in vascular mild cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490542},
doi = {10.1177/13872877261490542},
pmid = {42842469},
issn = {1875-8908},
abstract = {BackgroundVascular mild cognitive impairment (vaMCI) is frequently accompanied by neuropsychiatric symptoms (NPS), particularly apathy, which are associated with white matter hyperintensities (WMH). N-acetylcysteine (NAC) combined with exercise may provide neuroprotective benefits.ObjectiveWe hypothesized that baseline frontal and global WMH burden would moderate the neuropsychiatric response to NAC plus exercise. We further hypothesized that the strongest domain-specific effects would be observed for apathy and affective dysregulation.MethodsParticipants with vaMCI were randomized to NAC (2400 mg daily) or placebo plus exercise for 6 months. WMH volumes were quantified using structural MRI. NPS were assessed using the Mild Behavioral Impairment Checklist (MBI-C) at baseline, 3 months, and 6 months. Negative binomial generalized linear mixed models examined WMH × time × treatment interactions. False discovery rate (FDR) correction was applied.ResultsFifty-one participants were included. Lower baseline frontal (β = 0.229, SE = 0.070, FDR-adjusted p = 0.007) and global (β = 0.258, SE = 0.080, FDR-adjusted p = 0.007) WMH volume was associated with greater reductions in NPS over 6 months in the NAC plus exercise group. This effect was driven by improvements in apathy (frontal: β = 0.186, SE = 0.076, FDR-adjusted p = 0.048; global: β = 0.207, SE = 0.089, FDR-adjusted p = 0.049).ConclusionsBaseline WMH burden moderates neuropsychiatric treatment response in vaMCI. These findings support the importance of optimizing care for cerebrovascular risk factors in this vulnerable population.},
}

@article {pmid42843100,
year = {2026},
author = {Zhu, Y and Jafari, Z and Kolb, BE and Mohajerani, MH},
title = {From pathogenesis to non-medical therapy: A review of exploring sensory and multi-sensory stimulation as a non-invasive treatment approach for Alzheimer's disease.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {107004},
doi = {10.1016/j.neubiorev.2026.107004},
pmid = {42843100},
issn = {1873-7528},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder, marked by the accumulation of amyloid-beta plaques, tau pathology, and synaptic dysfunction, ultimately leading to memory loss, cognitive decline, neuropsychiatric symptoms and neuronal degeneration that impairs daily functioning. Despite the availability of pharmacological treatments developed to slow down symptom progression, their clinical efficacy remains uncertain, and they are frequently associated with adverse side effects, underscoring the urgent demand for safer and more effective therapeutic alternatives. Non-pharmacological approaches, therefore, have been investigated and are considered promising alternative therapeutic strategies for AD. This paper outlines the pathological features and neural network changes that occur across the progression of Alzheimer's disease (AD), reviews the effects of different sensory stimulation approaches on reducing these AD-associated changes, and discusses the potential mechanisms underlying various sensory and multisensory stimulation interventions in mitigating AD-related symptoms. These sensory stimulation interventions, including 40 Hz Gamma Entrainment Using Sensory Stimulation [GENUS], Photobiomodulation, Bright Light Therapy, Music Therapy, Aromatherapy, Tactile Stimulation, and Multisensory Stimulation, are found to slow down the progression of AD by ameliorating multiple AD pathologies, enhancing cognitive function, promoting neuroplasticity, regulating sleep patterns, and reducing behavioural or neuropsychiatric symptoms. Crucially, this present work integrates both human and animal studies, aligning clinical outcomes with mechanistic insights derived from animal studies, thereby bridging preclinical and clinical research to promote the translation of sensory interventions into effective treatments for patients with AD.},
}

@article {pmid42843827,
year = {2026},
author = {Hall, J},
title = {Lessons from the history of antipsychotic discovery: part 3 - muscarinic mechanisms.},
journal = {BJPsych bulletin},
volume = {},
number = {},
pages = {1-4},
doi = {10.1192/bjb.2026.10267},
pmid = {42843827},
issn = {2056-4694},
abstract = {After more than seven decades in which antipsychotic drug development has been dominated by dopaminergic mechanisms, the recent emergence of a muscarinic receptor-based treatment represents a conceptual shift in the pharmacotherapy of psychosis. This article reviews the history and development of the first clinically effective non-dopaminergic antipsychotic, tracing its origins to unexpected behavioural effects observed during trials of muscarinic agonists developed for Alzheimer's disease. Early studies of the muscarinic agonist xanomeline demonstrated antipsychotic efficacy, but were limited by poor tolerability due to peripheral cholinergic adverse effects. Subsequent progress depended on the dissociation of central therapeutic effects from peripheral side-effects, through the combination of xanomeline with the peripherally restricted muscarinic antagonist trospium. The development of this treatment highlights several broader lessons for psychiatric drug discovery, including the value of revisiting previously abandoned compounds, the benefits of leveraging existing human safety data on the importance of early-phase translational research and the role of innovative companies.},
}

@article {pmid42844308,
year = {2026},
author = {Gandhi, SM and Patel, S and Haswani, NG and Wahab, S and Sabah, ZU and Kapoor, DU},
title = {RVG29-functionalized nanocarriers for brain-targeted therapy of neurodegenerative diseases: mechanisms, therapeutic advances, and translational perspectives.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42844308},
issn = {1432-1912},
abstract = {Neurodegenerative diseases (NDs) affect more than 55 million people worldwide, with this number projected to exceed 139 million by 2050 due to population aging. Alzheimer's disease (AD) accounts for 60-70% of dementia cases, while Parkinson's disease (PD) affects over 10 million individuals globally, highlighting the growing clinical and socioeconomic burden of these progressive neurological disorders. Effective treatment of AD, PD, amyotrophic lateral sclerosis (ALS), and related central nervous system disorders remains hindered by the blood-brain barrier (BBB), poor brain accumulation, rapid systemic clearance, and off-target toxicity. RVG29, a 29-amino-acid peptide derived from rabies virus glycoprotein, has emerged as a promising brain-targeting ligand because of its high affinity for nicotinic acetylcholine receptors expressed on neuronal and brain endothelial cells. This review critically examines the mechanisms underlying RVG29-mediated receptor-dependent BBB transcytosis, intracellular trafficking, and neuronal uptake. Furthermore, it comprehensively evaluates RVG29-functionalized lipid nanoparticles, polymeric nanoparticles, exosomes, biomimetic nanocarriers, micelles, inorganic nanostructures, and hybrid systems with respect to their physicochemical characteristics, targeting efficiency, therapeutic efficacy, and safety. Collectively, these nanocarriers demonstrate enhanced BBB penetration, increased drug accumulation in diseased brain regions, and efficient delivery of small molecules, genes, mRNA, and siRNA. By modulating oxidative stress, neuroinflammation, protein aggregation, ferroptosis, and mitochondrial dysfunction, RVG29-engineered nanocarriers provide significant neuroprotection with favorable biocompatibility and minimal immunogenicity. Despite these advances, challenges related to large-scale manufacturing, peptide stability, regulatory approval, and long-term biosafety must be addressed to facilitate their clinical translation as precision neurotherapeutics.},
}

@article {pmid42837878,
year = {2026},
author = {Mohan, R and Mali, S and Ilango, P and Jainulabdeen, J},
title = {Gather-excite attention-driven deep learning model for Alzheimer disease detection from MRIs using adaptive residual-DenseNet strategy.},
journal = {Psychiatry research. Neuroimaging},
volume = {364},
number = {},
pages = {112344},
doi = {10.1016/j.pscychresns.2026.112344},
pmid = {42837878},
issn = {1872-7506},
abstract = {In worldwide, Alzheimer's Disease (AD) is one of the leading cause of death and requires earlier diagnosis for timely and effective treatment management. Neuroimaging, particularly Magnetic Resonance Imaging (MRI) provides a promising solution to detect the AD at earlier stages. Timely detection of variations in brain is critical for enabling effective interventions and mitigating the progression of AD. However, manual analysis of MRI scans remains challenging and time-consuming due to structural complexity and variations across individuals. Subtle patterns and background noise often remain undetected with conventional methods, thereby limiting diagnostic accuracy. Computer-based techniques improve reliability, but MRI heterogeneity complicates feature extraction and prediction model development. To overcome the issues of conventional models, the research study proposes Gather-Excite Adaptive Residual-Densenet (GE-ARDNet) model for AD detection. Here, the MRI images are collected and progressed through GE-ARDNet that integrates the residual learning with dense connectivity to enhance feature propagation. The Gather-Excite model exploits contextual information using an attention strategy, focusing on discriminative regions associated with AD pathology. Model efficiency is improved by optimizing Residual-Densenet parameters with Renovated Parameter Masterpiece Optimizer (RPMO), ensuring robust feature learning and generalization. Finally, the cross-validation and independent analysis is validated, demonstrating its effectiveness of the proposed model.},
}

@article {pmid42838180,
year = {2026},
author = {Elfiky, AM and Shahy, EM and Mahmoud, AA},
title = {Probiotics Attenuate AlCl3-Induced Alzheimer's Disease via Gut-Brain Axis Modulation and Suppression of NF-κB/NLRP3 Neuroinflammation.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115532},
doi = {10.1016/j.physbeh.2026.115532},
pmid = {42838180},
issn = {1873-507X},
abstract = {Disruptions along the brain-gut-microbiota axis significantly contribute to Alzheimer's disease (AD) pathogenesis. This study evaluated the therapeutic potential of a multi-strain probiotic mixture in mitigating cognitive decline, neuroinflammation, and amyloid pathology in an AD rat model. In the present study, after induction of AD in rats by oral administration of AlCl3 (50 mg/kg) for 28 days, followed by oral treatment with a probiotic mixture (10[9] log CFU/ml) for 42 days. Behavioral assessments were conducted during the final week. Hippocampal tissues were obtained for histopathological and gene expression analyses and fecal samples were subjected to full-length 16S rRNA gene sequencing via Oxford Nanopore approach. Probiotics significantly improved AD-induced deficits in locomotor activity, exploratory behavior, and spatial recognition memory. Histological analysis revealed marked reductions in hippocampal β-amyloid deposition and substantial restoration of colonic mucosal barrier integrity. Microbiota profiling showed that probiotics reversed dysbiosis, significantly enriching beneficial genera (Blautia, Clostridium, Eubacterium). Blautia abundance was strongly negatively correlated with NF-κB expression. Mechanistically, probiotics suppressed neuroinflammation by down-regulating pro-inflammatory cascades TNF-α, NLRP3, IL-1β, and NF-κB activation. Furthermore, treatment suppressed amyloidogenic processing via decreased APP mRNA and enhanced Aβ clearance through upregulation of LRP1 and modulation of AGER. These findings provide integrative evidence that probiotics exert neuroprotective and immunomodulatory effects, supporting their translational potential as a preventive strategy against AD-related cognitive decline.},
}

@article {pmid42838381,
year = {2026},
author = {Rana, A and Mélanie, P and Van Amanda, L and Nathalie, BH},
title = {"Structural and Metabolic Reprogramming by Docosahexaenoic Acid in Neuronal Cell Models of Alzheimer's Disease".},
journal = {Biochimie},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.biochi.2026.10.005},
pmid = {42838381},
issn = {1638-6183},
abstract = {Docosahexaenoic acid (DHA; 22:6n-3) is the most abundant omega-3 polyunsaturated fatty acid in the mammalian brain and an essential structural component of neuronal membranes. Several research studies indicate that DHA plays critical roles in maintaining membrane lipid composition, synaptic integrity, mitochondrial function, and metabolic homeostasis, processes that are disrupted in Alzheimer's disease (AD) and other neurodegenerative disorders. Because brain DHA availability depends largely on systemic metabolism and liver-brain communication, alterations in DHA homeostasis have been proposed as contributing factors to AD pathogenesis. In vitro neuronal culture models have been pivotal in investigating the molecular and biochemical mechanisms underlying DHA-mediated neuroprotection under disease-related conditions. This mini review summarizes how DHA treatment modulates cellular membrane organisation, synaptogenesis and cytoskeletal integrity, and its neuroprotective role in in vitro neuronal models of AD. Collectively, the literature supports DHA as a key modulator of the structure and metabolic mechanisms at the cellular level and supports the hypothesis that its greatest benefit may occur as a preventive or early-stage intervention. Although effective therapeutic interventions are still lacking, and more investigations integrating next-generation cellular models are still needed, these models provide crucial insights for developing targeted therapeutic applications in AD.},
}

@article {pmid42838860,
year = {2026},
author = {Na, S and Kim, HS and Kim, GH and Kwon, OD and Shim, YS and Lee, CN and Rhee, HY and Choi, H and Hong, YJ and Lee, J and Moon, SY and Park, KH},
title = {Memantine in Korean Alzheimer's disease: A prospective real-world REMIND study.},
journal = {International psychogeriatrics},
volume = {},
number = {},
pages = {100298},
doi = {10.1016/j.inpsyc.2026.100298},
pmid = {42838860},
issn = {1741-203X},
abstract = {OBJECTIVES: Prospective real-world evidence on memantine in Korean patients with Alzheimer's disease remains limited. This study evaluated its real-world effectiveness and tolerability over 24 weeks of routine clinical practice.

DESIGN & SETTING: Multicenter, prospective, single-arm observational study conducted at twelve university-affiliated tertiary hospitals in Korea.

PARTICIPANTS: Patients aged ≥ 50 years with Alzheimer's disease (Mini-Mental State Examination score of 5-20 and either a Clinical Dementia Rating of 2-3 or a Global Deterioration Scale score of 4-7) initiated on memantine (Ebixa®) 10-20 mg/day. The safety set comprised 401 patients and the effectiveness set 339.

MEASUREMENTS: The primary outcome was change in the Clinical Dementia Rating global score at Week 24. Secondary outcomes were changes in the Clinical Dementia Rating Sum of Boxes, Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview at Weeks 12 and 24, together with treatment persistence and adverse events.

RESULTS: At Week 24, 86.6% of 339 effectiveness-set patients remained within their baseline Clinical Dementia Rating category, 10.5% worsened, and 2.9% improved. Mini-Mental State Examination scores increased and Neuropsychiatric Inventory total scores decreased at both visits (all p < 0.05), with small standardized effect sizes (absolute d 0.08-0.17). Zarit Burden Interview scores increased at both visits. Treatment persistence was 89.5% at Week 24, and drug-related adverse events occurred in 17.7%.

CONCLUSION: Over 24 weeks of memantine treatment, most patients remained within their baseline Clinical Dementia Rating category, cognitive and neuropsychiatric scores showed small within-patient changes, caregiver burden increased, and tolerability was acceptable.},
}

@article {pmid42840164,
year = {2026},
author = {Tsai, E and Wang, Z and Truglio, J},
title = {A computational-first proof-of-concept for dual-function metal chelation and aggregate neutralization in an Aβ42 Drosophila model.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1912315},
pmid = {42840164},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) pathology is amplified by a self-reinforcing metal-Aβ-ROS axis, in which redox-active Cu and Fe bound to Aβ N-terminal histidines catalyze Fenton-like ROS generation and accelerate aggregation. Existing single-target interventions - anti-amyloid antibodies, antioxidants, metal-protein attenuating compounds, aggregation inhibitors, and photooxygenation catalysts - each address only one node of this loop. We used a computational-first framework to evaluate a dual-function strategy targeting two connected points of the axis: upstream redox-active metal sequestration by maltol, and downstream photodynamic modification of Aβ aggregates via endogenous protoporphyrin IX (PpIX), generated from 5-aminolevulinic acid (5-ALA) under 400 nm illumination. Drosophila experiments served as functional validation, testing whether this combined intervention improved Aβ42-associated behavioral and survival outcomes and was tolerated in wild-type (WT) flies. DFT calculations (B3LYP-D3BJ/def2-SVP//def2-TZVP, CPCM/SMD water) showed deprotonated maltol localizes oxygen-donor electron density comparable to deprotonated deferiprone, and forms a converged, solvent-stabilized Fe(III)-maltol complex. Cu(II) and Zn(II) coordination was weak and geometrically incomplete, indicating an Fe-preferential rather than broadly nonspecific chelation profile; the study does not demonstrate protection against Cu(II)-mediated ROS. Time-dependent DFT predicted PpIX excitations spanning the visible/near-UV range consistent with photosensitizer behavior, and docking against Aβ42 fibril 5OQV showed PpIX engaged the central hydrophobic/turn surface more strongly than chlorin e6 or maltol. In a pan-neuronal Aβ42 Drosophila model, dual treatment improved climbing performance (p = 2.39 × 10[-3] vs. untreated Aβ42) and extended lifespan (log-rank p = 6.04 × 10[-13]; median survival ∼40 d); WT + Treatment flies appeared tolerant, though no formal statistical contrast was pre-specified. Treatment-group ThT amyloid burden was not measured, so no amyloid-reduction claim is made. Because chelation-only and 5-ALA/light-only arms were not included, we cannot attribute improvement to either intervention alone and cannot make a formal claim of additive or interactive effects between the two intervention components. The combined intervention was associated with improved behavioral and survival outcomes in the Aβ42 Drosophila model. Because the present study lacks single-intervention controls and treatment-group pathological measurements, these findings do not establish the mechanism responsible for the observed functional improvement. The study illustrates how ground-state, excited-state, and docking calculations can jointly inform a computationally motivated intervention tested in a tractable organismal model.},
}

@article {pmid42840889,
year = {2026},
author = {Praveen, R and Gadaleta, A and Spada, G and Miniero, DV and Reza, A and Chaudhari, TY and Rahman, A and Catto, M and Hoda, N},
title = {Design, synthesis, and biological evaluation of naphthalimide derivatives as dual monoamine oxidase-B and amyloid-β aggregation inhibitors for Alzheimer's disease.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42840889},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder with multifactorial pathogenesis. Amyloid beta (Aβ) and monoamine oxidase (MAO) are among the key therapeutic targets for its treatment. In this investigation, a series of 18 new naphthalimide-based derivatives were synthesized and assessed for multitarget activity against hAChE, esBuChE, MAO-A, MAO-B, Aβ, and paired helical fragment 6 (PHF6) aggregation. The screened compounds predominantly exhibited dual inhibition of MAO-B and Aβ aggregation to counteract oxidative stress and plaque formation. Among the tested compounds, P12 and P17 were found to have remarkable inhibition against Aβ, with 83% and 91% inhibition, respectively, compared to the reference compound quercetin (75% inhibition). The compound P10 was the most effective MAO-B inhibitor, with an IC50 value of 3.09 ± 0.10 µM. Cytotoxicity studies in SH-SY5Y cells confirmed that compounds were non-toxic up to 25 µM. Additionally, the neuroprotection assays revealed that P10 was capable of reducing oxidative stress effectively against H2O2-induced toxicity, while P12 showed superior protection against Aβ-induced neurotoxicity in SH-SY5Y cells. Furthermore, in silico investigations provided structural insights into the predicted ligand-target interaction modes and dynamic behavior of the selected compounds with MAO-B and monomeric Aβ1-42. Consequently, all these findings underscore that naphthalimide derivatives are promising dual inhibitors of amyloid-β aggregation and MAO-B and have potential for further development as MTDLs for AD.},
}

@article {pmid42840967,
year = {2026},
author = {Brenner, M and Sharma, A and Wang, P},
title = {Ionizing radiation and Alzheimer's disease: epidemiology, mechanisms, and eCIRP-mediated tau pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1961728},
pmid = {42840967},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/epidemiology/metabolism/etiology/pathology ; Animals ; *Radiation, Ionizing ; *RNA-Binding Proteins/metabolism ; *tau Proteins/metabolism ; },
abstract = {As human radiation exposure expands through medical imaging, nuclear industry growth, and the acceleration of crewed space exploration, understanding the molecular mechanisms linking radiation to Alzheimer's disease (AD) is becoming an increasingly urgent priority. Here, we review epidemiological, mechanistic, and therapeutic evidence for a relationship between ionizing radiation and AD, focusing on a neuroinflammatory pathway centered on extracellular cold-inducible RNA-binding protein (eCIRP). Epidemiological support comes from occupational cohorts of nuclear workers and studies linking residential radon to AD mortality; a meta-analysis of 18 studies finds an 11% increased all-cause dementia risk per 100 mSv. Mechanistically, ionizing radiation generates DNA double-strand breaks and reactive oxygen species that activate the ataxia-telangiectasia mutated (ATM) kinase and trigger rapid microglial activation, and causes the nuclear-to-cytoplasmic translocation and extracellular release of the danger-associated molecular pattern eCIRP. Released eCIRP activates neuronal cyclin-dependent kinase 5 (Cdk5), resulting in AD-like tau phosphorylation. This pathway is validated by loss-of-function studies in CIRP-knockout mice and pharmacological blockade with the eCIRP inhibitor C23. Beyond tau phosphorylation, eCIRP drives mitochondrial dysfunction and ferroptosis in myeloid cells and activates endothelial cell death pathways that may compromise blood-brain barrier integrity. eCIRP links radiation-induced neuroinflammation to tau-driven neurodegeneration, and eCIRP inhibitors warrant investigation for both radiation-induced cognitive dysfunction and sporadic AD, where eCIRP is similarly elevated. Translating these mechanistic insights into eCIRP-targeted therapies and validated biomarkers could open a new front in the prevention and treatment of these prevalent and debilitating disorders.},
}

Humans
*Alzheimer Disease/epidemiology/metabolism/etiology/pathology
Animals
*Radiation, Ionizing
*RNA-Binding Proteins/metabolism
*tau Proteins/metabolism

@article {pmid42841310,
year = {2026},
author = {Pang, M and Brothers, HM and O'Gorman, J and Murphy, J and Zabar, Y and Lasky, T and Shen, C and Rubino, I and Knopman, D},
title = {Longitudinal clinical outcomes after amyloid clearance in aducanumab phase 3 studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71758},
pmid = {42841310},
issn = {1552-5279},
support = {//Biogen/ ; },
mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Double-Blind Method ; Female ; Male ; Treatment Outcome ; Positron-Emission Tomography ; Aged ; *Amyloid beta-Peptides/metabolism ; Longitudinal Studies ; *Amyloid/metabolism ; },
abstract = {INTRODUCTION: Anti-amyloid antibody clinical trials with a high proportion of participants reaching treatment-related amyloid clearance (TRAC) had positive clinical outcomes. We evaluated the aducanumab phase 3 program to determine whether TRAC during the double-blind period was likewise associated with clinical benefit.

METHODS: We pooled ENGAGE and EMERGE (E/E) aducanumab-treated participants in the amyloid positron emission tomography substudy who continued into the long-term extension ≤ 134 weeks (continuously treated population) and/or returned to the EMBARK redosing study 0.7 to 2.5 years after termination of E/E (treatment gap population). Clinical outcomes were stratified by week 78 TRAC status.

RESULTS: TRAC participants had less clinical decline at week 78, week 134, and EMBARK baseline than non-TRAC participants. Post-TRAC, clinical decline was heterogeneous; approximately two thirds of TRAC participants had annualized decline of < 1 point on Clinical Dementia Rating Sum of Boxes.

DISCUSSION: In these exploratory analyses, week 78 TRAC status was associated with better clinical outcomes.

CLINICAL TRIAL REGISTRATION: NCT02484547, NCT02477800, NCT04241068.},
}

Humans
*Antibodies, Monoclonal, Humanized/therapeutic use
*Alzheimer Disease/drug therapy/diagnostic imaging
Double-Blind Method
Female
Male
Treatment Outcome
Positron-Emission Tomography
Aged
*Amyloid beta-Peptides/metabolism
Longitudinal Studies
*Amyloid/metabolism

@article {pmid42841389,
year = {2026},
author = {Chapel, JM and Tysinger, B and Pourmand, H and Goldman, D and Aisen, P and , },
title = {The value of timely treatment with anti-amyloid therapy for Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71819},
pmid = {42841389},
issn = {1552-5279},
support = {U01AG086827/AG/NIA NIH HHS/United States ; //USC Schaeffer Center for Health Policy & Economics/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/economics ; Disease Progression ; Aged ; Female ; Treatment Delay ; Quality of Life ; United States ; Male ; Health Care Costs ; Cost-Benefit Analysis ; },
abstract = {INTRODUCTION: Anti-amyloid therapies can slow Alzheimer's disease (AD) progression; diagnostic and treatment delays might reduce their value.

METHODS: Using dynamic microsimulation, we estimated the gross societal value of anti-amyloid treatment for Americans with early symptomatic AD. A treatment scenario slowed the rate of clinical progression by 29% over individuals' remaining lifetime (baseline mean age: 73.0); earlier treatment initiated 2 years earlier.

RESULTS: Treatment generated $104,885 (95% CI: $99,291, $110,479) in gross societal value over an individual's lifetime, including quality-of-life gains, reduced caregiving burden, and medical cost offsets driven by reduced nursing home use and Medicaid spending. Earlier treatment increased value 32%; this rose to 71% if treatment effects are also stronger (36% slowing) in earlier AD stages. Scenarios with 4-year effect duration yielded $49,122 (treatment) and $56,385 (earlier treatment).

DISCUSSION: Timely treatment consistently increased long-term societal value. The findings provide a benchmark against which treatment implementation costs can be weighed.},
}

Humans
*Alzheimer Disease/drug therapy/economics
Disease Progression
Aged
Female
Treatment Delay
Quality of Life
United States
Male
Health Care Costs
Cost-Benefit Analysis

@article {pmid42841516,
year = {2026},
author = {Wu, D and Nie, MT and Lin, J and Liu, Y and Wang, Y and Chu, M and Zheng, L and Zhao, J},
title = {Rifaximin ameliorates memory impairment and Alzheimer's pathological changes in APP/PS1 mice associated with changes in the gut microbiome-bile acids-serum metabolites networks.},
journal = {British journal of pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1111/bph.70643},
pmid = {42841516},
issn = {1476-5381},
support = {2022MHPY02//Minhang Hospital of Fudan University/ ; 2025MHBJ03//Minhang Hospital of Fudan University/ ; MGWXK2023-04//Minhang Hospital of Fudan University/ ; 2024DR010//China University Industry-Academia-Research Innovation Fund/ ; },
abstract = {BACKGROUND AND PURPOSE: Modifying the brain-gut-microbiota axis has emerged as a promising therapeutic strategy against Alzheimer's disease (AD). Whether rifaximin, a non-absorbed and non-systemic antibiotic, can be applied to the treatment of AD remains unexplored. In this study, we investigated the effects of rifaximin using a APP/PS1 double-transgenic mouse model of AD.

EXPERIMENTAL APPROACH: Six-month-old male APP/PS1 mice were administered saline or rifaximin (100 mg·kg[-1]) via oral gavage for 2 months. Gut microbiota composition and metabolites were subsequently analysed to elucidate the underlying mechanisms of rifaximin in AD.

KEY RESULTS: Rifaximin modified gut microbiota composition, increasing abundance of Akkermansia muciniphila and Christensenellaceae, while decreasing abundance of Clostridia_UCG-014, Muribaculaceae, Lachnospiraceae, Turicibacter, Eubacterium_xylanophilum_group, Alistipes, Bacteroides_acidifaciens and Eubacterium_brachy groups. Furthermore, rifaximin alleviated memory impairment in APP/PS1 mice, decreased amyloid-β (Aβ) burden and secondary neuroinflammation and attenuated neuronal death and synaptic dysfunction. Metabolomic analysis revealed that rifaximin altered the profile of gut bile acids by decreasing the concentrations of primary (cholic acid and taurocholic acid) and secondary (taurodeoxycholic acid and taurolithocholic acid) bile acids. Additionally, rifaximin enhanced tryptophan metabolism, shown by increased serum 5-HT concentrations. Both microbial and metabolic shifts were closely correlated with gut microbiota composition.

CONCLUSIONS AND IMPLICATIONS: Our results showed that rifaximin alleviated spatial working and short-term recognition memory impairment and mitigated Alzheimer's-like pathological changes in APP/PS1 mice, effects accompanied by alterations in the gut microbiota-intestinal bile acid profile-serum metabolites network. Rifaximin could provide a new therapeutic approach to the treatment of AD.},
}

@article {pmid42831108,
year = {2026},
author = {Hung, KC and Yu, TS and Liu, PH and Lai, YC and Chen, IW},
title = {GLP-1 Receptor Agonists Versus DPP-4 Inhibitors and Incident Dementia Risk in COVID-19 Survivors with Type 2 Diabetes: A Target Trial Emulation Study.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {638249},
pmid = {42831108},
issn = {1177-8881},
mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; *COVID-19/complications/epidemiology ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects ; *Dementia/epidemiology ; *Hypoglycemic Agents/therapeutic use ; Male ; Female ; Aged ; Middle Aged ; Incidence ; Survivors ; },
abstract = {PURPOSE: Type 2 diabetes mellitus (T2DM) and COVID-19 are independently associated with an elevated risk of dementia, and COVID-19 survivors with T2DM may represent a clinically vulnerable population in whom metabolic, inflammatory, and vascular factors coexist. However, whether antidiabetic treatment choice is associated with incident dementia risk in this population remains unknown.

METHODS: In this target trial emulation using the TriNetX US Collaborative Network, we compared COVID-19 survivors aged ≥50 years with T2DM initiating glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy with those initiating dipeptidyl peptidase-4 inhibitor (DPP-4i) therapy between January 1, 2020 and December 31, 2024. We applied an active-comparator, new-user design with a 90-day survivor landmark and 1:1 propensity score matching. The primary outcome was incident all-cause dementia (a composite of vascular dementia, Alzheimer's disease, and other dementias). Secondary outcomes included dementia subtypes, mild cognitive impairment, glycemic outcomes, and all-cause mortality.

RESULTS: After matching, 25,263 patients per group were followed for up to 6 years (median, 919 days [GLP-1RA] vs 955 days [DPP-4i]). GLP-1RA initiation was associated with a lower hazard of incident dementia (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.58-0.72), vascular dementia (HR, 0.67; 95% CI, 0.52-0.85), and Alzheimer's disease (HR, 0.74; 95% CI, 0.59-0.93), as well as more favorable glycemic control and lower all-cause mortality (HR, 0.63; 95% CI, 0.59-0.68). The estimate for mild cognitive impairment was borderline (HR, 0.87; 95% CI, 0.75-1.00) and not consistently supported across sensitivity analyses. The association with incident dementia remained evident after the 6-month landmark analysis (HR, 0.66; 95% CI, 0.58-0.75) and was consistent across sensitivity and subgroup analyses.

CONCLUSION: Among COVID-19 survivors with T2DM, GLP-1RA initiation was associated with a lower hazard of incident dementia than DPP-4i initiation. These hypothesis-generating results warrant confirmation before they can be used to inform clinical decision-making.},
}

Humans
*Diabetes Mellitus, Type 2/drug therapy
*Glucagon-Like Peptide-1 Receptor Agonists
*COVID-19/complications/epidemiology
*Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects
*Dementia/epidemiology
*Hypoglycemic Agents/therapeutic use
Male
Female
Aged
Middle Aged
Incidence
Survivors

@article {pmid42831322,
year = {2026},
author = {Xie, S and Zheng, B and Li, M and Zheng, B and Shen, G and Xiang, X and Chen, L},
title = {Sciadonic acid ameliorates cognitive impairment in APP/PS1 mice with concomitant modulation of gut microbiota and brain metabolism.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo01986b},
pmid = {42831322},
issn = {2042-650X},
abstract = {Sciadonic acid (SCA) is a fatty acid derived from Torreya grandis oil with known anti-inflammatory and antioxidant properties; however, its role in Alzheimer's disease (AD) remains undefined. In this study, oral SCA administration to APP/PS1 transgenic mice significantly improved spatial learning and memory, as assessed by Morris water maze and Y-maze tests. Histological examination revealed reduced neuronal loss, preserved neuropil architecture, and diminished Aβ plaque burden in the hippocampus and cerebral cortex. SCA treatment enhanced antioxidant capacity, as indicated by elevated superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, alongside decreased malondialdehyde (MDA) and nitric oxide (NO) levels. Furthermore, SCA restored colonic mucosal integrity and suppressed pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Gut microbiota analysis revealed reversal of dysbiosis, with an increased Bacillota/Bacteroidetes ratio, enrichment of beneficial taxa such as Lactobacillus, and elevated short-chain fatty acid (SCFA) levels. Non-targeted hippocampal metabolomics identified modulation of 16 metabolites, predominantly in taurine and hypotaurine, and pyrimidine pathways. Collectively, SCA administration was associated with cognitive and neuropathological improvements alongside alterations in gut microbiota and hippocampal metabolism.},
}

@article {pmid42831987,
year = {2026},
author = {Ma, T and Zhou, H and Liu, Y and Cheng, X and Li, M},
title = {Electroacupuncture Targeting the NLRP3 Inflammasome in Senescence‑associated Cognitive Impairment: Mechanistic Synthesis and Meta‑analysis of Clinical Randomized Controlled Trials.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42831987},
issn = {1573-6903},
mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Electroacupuncture/methods ; *Inflammasomes/metabolism ; *Cognitive Dysfunction/therapy/metabolism ; Animals ; Randomized Controlled Trials as Topic/methods ; *Aging/metabolism ; },
abstract = {Global population aging leads to a growing clinical demand for interventions against age-related cognitive decline (ARCD), including mild cognitive impairment (MCI, termed senescence-associated cognitive impairment [SACI] in this review)-a prodromal pathological stage preceding Alzheimer's disease (AD) and vascular dementia. Chronic microglia-mediated neuroinflammation, predominantly triggered by excessive NLRP3 inflammasome activation, acts as a key upstream mediator of hippocampal neuronal injury and gradual cognitive decline in preclinical aging models.Manual acupuncture and electroacupuncture (EA) exert reproducible neuroprotective effects against cognitive deficits, yet a comprehensive, multi-layered regulatory framework unifying NLRP3-centered molecular mechanisms of acupuncture remains absent from current literature. This review systematically summarizes NLRP3‑dependent pathological cascades in SACI and outlines four synergistic signaling axes through which acupuncture may modulate excessive NLRP3‑dependent inflammatory responses to potentially alleviate neurotoxic inflammatory injury.Persistent overactivation of the NLRP3 inflammasome triggers self-amplifying inflammatory feedback cycles in hippocampal tissue through four interrelated pathological processes: impaired autophagic clearance, disrupted mitochondrial homeostasis, persistent endoplasmic reticulum (ER) stress, and caspase-1/GSDMD-mediated neuronal pyroptosis.Acupuncture counteracts NLRP3-dependent neural injury through synergistic multi-target modulation: (1) activation of AMPK/mTOR signaling to restore defective autophagy; (2) suppression of the ROS-TXNIP cascade to block NLRP3 transcriptional priming and protein oligomerization; (3) phenotypic reprogramming of microglia from pro-inflammatory M1 toward anti-inflammatory M2 states; (4) inhibition of pyroptotic execution by blunting caspase-1 maturation and GSDMD proteolytic cleavage. Collectively, available pre‑clinical evidence suggests these signaling axes constitute a bidirectionally‑interconnected hypothetical protective network that may mitigate chronic neuroinflammation.A meta analysis integrating nine eligible randomized controlled trials (published 2015-2025) involving 614 participants was performed. After subject dropout, 599 participants completed the studies. Pooled analyses of heterogeneous acupuncture/electroacupuncture RCTs revealed that intervention was associated with short‑term improvements in MoCA and MMSE scores and reduction in peripheral pro‑inflammatory cytokine IL‑6. Pooled effect sizes were moderately larger in MCI subgroups compared with patients with early AD. Nevertheless, substantial methodological heterogeneity existed across included trials, and these short term observational findings cannot confirm durable disease modifying benefits.Severe methodological heterogeneity across existing trials-including inconsistent acupoint prescriptions, divergent EA stimulation parameters, and variable treatment cycles-impairs cross-study comparability and translational reproducibility. Herein, we synthesize high‑quality preclinical and clinical evidence to propose a provisional consensus‑oriented translational reference protocol for electroacupuncture, intended for standardized mechanistic research rather than routine clinical intervention.Collectively, the NLRP3 inflammasome constitutes a tractable therapeutic target for acupuncture-mediated SACI intervention. Acupuncture exerts pleiotropic neuroprotection by dampening NLRP3-dependent neuroinflammation, alongside complementary NLRP3-independent regulatory pathways. This review‑meta‑analysis provides preliminary translational theoretical evidence for a provisional electroacupuncture intervention framework targeting NLRP3‑mediated neuroinflammation in MCI and early‑AD. Future high‑quality, multi‑center RCTs are warranted to validate these preliminary findings.},
}

Humans
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Electroacupuncture/methods
*Inflammasomes/metabolism
*Cognitive Dysfunction/therapy/metabolism
Animals
Randomized Controlled Trials as Topic/methods
*Aging/metabolism

@article {pmid42832237,
year = {2026},
author = {Estragués-Gázquez, I and Contador, J and Martínez, LD and Fernández-Lebrero, A and García-Escobar, G and Navalpotro-Gómez, I and Grau-Rivera, O and Iaccarino, G and Manero-Borràs, RM and Ortiz-Romero, P and Hernández-Villamizar, F and Torres-Torronteras, J and de Diego-Osaba, M and Blasco-Forniés, H and Jiménez-Moyano, E and Hernández, JJ and Padrós, A and Del Campo, M and Puig-Pijoan, A and Suárez-Calvet, M},
title = {Earlier Disclosure of Blood-Based Biomarkers, Diagnostic Certainty, and Clinical Management: A Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
pmid = {42832237},
issn = {2168-6157},
abstract = {IMPORTANCE: Blood-based biomarkers show high performance for detecting Alzheimer disease (AD) pathology, but evidence on their impact on diagnostic certainty, clinical management, and emotional outcomes in routine care is limited.

OBJECTIVE: To determine whether earlier disclosure of plasma phosphorylated tau at threonine 217 (p-tau217) and neurofilament light chain (NfL) increases etiologic diagnostic certainty, influences clinical management, and affects emotional outcomes in individuals evaluated for cognitive symptoms.

This was a prospective randomized clinical trial conducted at a single memory clinic in Spain between February and October 2024, with 9 months of follow-up. Consecutive new outpatients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or mild dementia without a prior etiologic diagnosis were enrolled. Of 265 eligible participants, 220 were randomized to earlier disclosure of blood-based biomarkers at the 3-month visit or delayed disclosure at the 9-month visit.

INTERVENTION: Disclosure of blood-based biomarkers for AD pathology (p-tau217) and neurodegeneration (NfL) to the treating neurologist and participant, alongside standard clinical evaluation.

MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of participants achieving a very high-confidence etiologic diagnosis (≥90%). Secondary outcomes included changes in clinical management and emotional outcomes (anxiety, depression, perceived stress, and quality of life).

RESULTS: Among the 220 randomized participants (median [IQR] age, 73 [68-78] years; 123 [55.9%] women), baseline diagnoses were SCD (100 [45.5%]), MCI (68 [30.9%]), and mild dementia (52 [23.6%]). At 3 months, a very high-confidence etiologic diagnosis was achieved in 56 of 112 participants in the earlier-disclosure arm (50.0%) compared with 5 of 108 in the delayed-disclosure arm (4.6%) (P < .001). Diagnostic certainty converged after disclosure in both arms, except among participants with MCI, in whom higher certainty persisted in the earlier-disclosure arm. Earlier disclosure was associated with more frequent initiation of symptomatic AD treatment (16/112 [14.3%] vs 5/108 [4.6%]; difference, 9.7; 95% CI, 1.8 to 17.8; P = .01), fewer planned follow-up neuropsychological reassessments for diagnostic clarification (34/112 [30.4%] vs 57/108 [52.8%]; difference, -22.4; 95% CI, -34.4 to -9.4; P < .001), and more planned discharge from the memory clinic to primary care (35/112 [31.3%] vs 13/108 [12.0%]; difference, 19.2; 95% CI, 8.4 to 29.5; P < .001). Earlier disclosure was not associated with worse emotional outcomes.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, earlier disclosure of blood-based biomarkers increased etiologic diagnostic certainty and led to earlier, targeted clinical management without increasing emotional distress. These findings support the integration of blood-based biomarkers into memory clinic diagnostic pathways.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06246019.},
}

@article {pmid42834737,
year = {2026},
author = {Marshall, JPS and Harutyunyan, A and Ng, J and West, OM and Collins, JM and King, AE and Morizzi, J and Wright, P and Calkin, AC and Drew, BG and Jones, NC and Adlard, PA and Febbraio, MA and Henstridge, DC},
title = {Genetic and Pharmacological Targeting of Hsp72 Overexpression/Induction in an Alzheimer's Disease Mouse Model With Combined Amyloid and Tau Pathology.},
journal = {Journal of neuroscience research},
volume = {104},
number = {10},
pages = {e70161},
pmid = {42834737},
issn = {1097-4547},
support = {//Yulgilbar Foundation/ ; //Dementia Australia Research Foundation/ ; //Shine on Foundation/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology/drug therapy ; *tau Proteins/metabolism ; Male ; Mice, Transgenic ; *HSP72 Heat-Shock Proteins/genetics/metabolism/biosynthesis ; Female ; Disease Models, Animal ; Mice ; *Amyloid beta-Peptides/metabolism ; Brain/metabolism/pathology ; Mice, Inbred C57BL ; },
abstract = {Heat shock protein 72 (Hsp72), a stress-inducible member of the Hsp70 family, has been implicated in mitigating the pathogenic effects of amyloid-beta (Aβ) and tau pathology; both key factors associated with the development and progression of Alzheimer's disease (AD). However, no in vivo study has been conducted to investigate the ability of Hsp72 to provide benefit when both Aβ and tau pathology are present concurrently. This study set out to utilize a genetic approach (transgenic overexpression) and a pharmacological validation approach (BGP-15) to increase Hsp72 expression in mice exhibiting Aβ and tau pathology (5xFADxTg30 model). Our findings indicate that genetic Hsp72 overexpression did not significantly alter Aβ or tau burden, deficits in motor performance, or alterations to body composition in this model, but modestly improved survival rates (driven by findings in male mice) and altered anxiety-like behavior (driven by findings in female mice). Similarly, BGP-15 treatment was unable to rescue behavioral traits, motor deficits, body composition, or alleviate Aβ or tau accumulation, although this treatment also showed a trend towards enhancing survival (again in male mice) and altered anxiety-like behavior (specifically in female mice). While the 5xFADxTg30 mice demonstrated seizure susceptibility compared to WT mice, BGP-15 was unable to alleviate this trait. These findings were independent of any measurable increase in Hsp72 abundance in the brain in response to BGP-15. Together, these findings suggest a limited impact of genetic overexpression and pharmacological targeting of Hsp72 protein abundance in this combined Aβ and tau model, although some sex-specific differences are noted.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology/drug therapy
*tau Proteins/metabolism
Male
Mice, Transgenic
*HSP72 Heat-Shock Proteins/genetics/metabolism/biosynthesis
Female
Disease Models, Animal
Mice
*Amyloid beta-Peptides/metabolism
Brain/metabolism/pathology
Mice, Inbred C57BL

@article {pmid42834854,
year = {2026},
author = {Zhang, X and Xiong, YJ and Lv, T and Chen, Y},
title = {Trends in Population-Level Mortality Rates for Deaths With Both Alzheimer's Disease and Cancer Recorded on Death Certificates Among U.S. Adults Aged ≥ 65 Years, 1999-2023.},
journal = {Nursing open},
volume = {13},
number = {10},
pages = {e70897},
pmid = {42834854},
issn = {2054-1058},
support = {2025HY1587//Zhejiang Provincial Health Industry Science and Technology Program/ ; },
mesh = {Humans ; *Death Certificates ; Aged ; *Alzheimer Disease/mortality ; United States/epidemiology ; Female ; Male ; *Neoplasms/mortality ; Aged, 80 and over ; Cause of Death/trends ; *Mortality/trends ; },
abstract = {AIM: To examine temporal trends and demographic and geographic variation in population-level rates of deaths with both Alzheimer's disease (AD) and cancer recorded on death certificates among U.S. adults aged ≥ 65 years from 1999 to 2023.

DESIGN: A population-based descriptive time-trend study using multiple-cause-of-death data.

DATA SOURCES: National mortality data from the CDC WONDER (1999-2023).

REVIEW METHODS: Death certificates for U.S. residents aged ≥ 65 years recording both AD (G30) and malignant neoplasms (C00-C97) were included. Age-adjusted mortality rates (AAMRs) were standardized to the 2000 U.S. population; age-group analyses used age-specific crude mortality rates. Joinpoint regression estimated annual percent changes (APCs) and average annual percent changes (AAPCs), with analyses stratified by demographic and geographic characteristics.

RESULTS: Annual deaths increased from 4764 in 1999 to 6240 in 2023, while the overall AAMR declined from 13.96 to 12.05 per 100,000 (AAPC -0.73%, 95% CI -1.39 to -0.06). Significant declines occurred among males, adults aged 75 -84 years, non-Hispanic Black populations, and residents of the Northeast and Midwest, whereas a significant increase occurred among Hispanic populations. Full-period trends among females and non-Hispanic Other populations were not statistically significant. Neither metropolitan nor nonmetropolitan areas showed a significant trend during 1999-2020.

CONCLUSION: The overall age-adjusted death-certificate mortality rate declined modestly despite increasing annual death counts, with descriptive variation across demographic and geographic groups.

The findings highlight the relevance of coordinated geriatric and oncology nursing assessment and care planning for older adults with complex health needs. Nurses may play an important role in identifying cognitive, functional, treatment-related, and caregiver needs and facilitating multidisciplinary care. These descriptive findings identify areas for clinical attention but do not demonstrate the effectiveness of specific nursing interventions. WHAT PROBLEM DID THE STUDY ADDRESS?: Limited evidence exists on long-term population-level trends in deaths with both AD and cancer recorded on death certificates. WHAT WERE THE MAIN FINDINGS?: The overall age-adjusted mortality rate declined modestly while annual death counts increased. Subgroup-specific trends varied, but no formal between-group comparisons were performed. WHERE AND ON WHOM WILL THE RESEARCH HAVE AN IMPACT?: The findings are relevant to clinicians, policymakers, and public health practitioners involved in the care of older adults with multimorbidity, particularly in underserved populations.

REPORTING METHOD: This study adheres to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines.

No Patient or Public Contribution. This study used publicly available, de-identified mortality data and did not involve direct patient or public participation.},
}

Humans
*Death Certificates
Aged
*Alzheimer Disease/mortality
United States/epidemiology
Female
Male
*Neoplasms/mortality
Aged, 80 and over
Cause of Death/trends
*Mortality/trends

@article {pmid42835365,
year = {2026},
author = {Shan, SY and Bai, JM and Tian, Y and Shen, YF and Zhang, YX and Cheng, YH and Liu, Y and Ning, HY and Min, DY and Ren, L and Xiao, HH},
title = {Icariside II protects against neuronal injury by modulating PI3K/AKT-dependent mitochondrial dynamics and apoptosis in Alzheimer's disease models.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1911518},
pmid = {42835365},
issn = {1663-9812},
abstract = {INTRODUCTION: Icariside II (ICS II), a major bioactive flavonoid metabolite from Epimedium, has been reported to exert neuroprotective effects, but its role in regulating mitochondrial dysfunction-related neuronal injury in Alzheimer's disease (AD) has not been fully clarified.

METHODS: In this study, we administered ICS II to APP/PS1 transgenic mice and to two neuronal cell models of AD-like injury (Aβ-exposed HT22 cells and APP-overexpressing N2a cells). We evaluated cognitive behaviour, histopathological changes, Aβ burden, neuronal apoptosis, mitochondrial membrane potential (ΔΨm), mitochondrial reactive oxygen species (mtROS) levels, mitochondrial morphology and dynamics (including fragmentation, mitofusin-2 (Mfn2) expression, and dynamin-related protein 1 (Drp1) phosphorylation), as well as cytochrome c (Cyt c) release and caspase-3 activity. RNA-sequencing analysis of hippocampal tissue and pharmacological inhibition with the PI3K inhibitor LY294002 were employed to probe the involvement of the PI3K/AKT signalling pathway.

RESULTS AND DISCUSSION: In vivo, ICS II improved cognitive performance, ameliorated hippocampal and cortical histopathological damage, decreased Aβ immunoreactivity, and reduced neuronal apoptosis. RNA-sequencing analysis suggested the involvement of PI3K/AKT signaling in the response to ICS II treatment. In vitro, ICS II increased cell viability, reduced oxidative stress, and inhibited apoptosis. These effects were associated with increased PI3K expression and AKT phosphorylation, restoration of ΔΨm, reduced mtROS accumulation, restored mitochondrial morphology (e.g., alleviated fragmentation, reduced punctate fragments, and increased mitochondrial length), decreased Cyt c release, increased Mfn2 expression, and decreased Drp1 phosphorylation at Ser616 and caspase-3 levels. Notably, co-treatment with LY294002 largely abolished these protective effects, indicating that PI3K/AKT signaling is functionally involved in this process. Taken together, our findings suggest that ICS II protects against AD-related neuronal injury are closely associated with PI3K/AKT-dependent regulation of mitochondrial dynamics and apoptosis, thereby providing a mechanistic foundation for further exploration of ICS II as a natural product-derived candidate for AD intervention.},
}

@article {pmid42835402,
year = {2026},
author = {Zhang, R and Li, L and Tang, J and Hu, S and Zhang, Q and Tan, J},
title = {Ultrasound neuromodulation in brain disorders: from mechanotransduction mechanisms to clinical translation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1942293},
pmid = {42835402},
issn = {1662-4548},
abstract = {Brain disorders impose a major global health burden, yet current pharmacological and neuromodulation therapies are often constrained by invasiveness, limited spatial precision, poor access to deep brain structures, or insufficient long-term efficacy. Non-invasive ultrasound neuromodulation has emerged as a promising approach combining high spatial resolution, deep tissue penetration, and reversible modulation. Its biological effects arise from multiscale mechanotransduction involving membrane deformation, mechanosensitive ion channels, intracellular calcium signaling, glial regulation, and neurovascular coupling. Together, these processes modulate neuronal excitability, synaptic plasticity, network connectivity, neuroinflammation, and cerebral perfusion. Preclinical studies support its therapeutic potential across neurological and psychiatric disorders, while early clinical studies indicate short-term tolerability and preliminary target engagement in Alzheimer's disease, Parkinson's disease, and depression. Emerging approaches, including individualized treatment planning, closed-loop stimulation, and sonogenetics, may further improve the precision and cellular specificity of ultrasound neuromodulation. This review summarizes the physical principles and cellular mechanisms of ultrasound neuromodulation, evaluates its therapeutic and clinical applications, and discusses key challenges and future directions, including personalized stimulation, closed-loop systems, sonogenetics, and disease-modifying strategies.},
}

@article {pmid42836463,
year = {2026},
author = {da Silva, JMA and Kümmerle, AE and Rodrigues, DA and Bolognesi, ML and Milelli, A and Lima, LM and de Sena Murteira Pinheiro, P},
title = {Recent advances of GPR40 agonists as potential anti-Alzheimer's agents.},
journal = {Future medicinal chemistry},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/17568919.2026.2732260},
pmid = {42836463},
issn = {1756-8927},
abstract = {Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disorder involving metabolic dysfunction, neuroinflammation, mitochondrial impairment, synaptic failure, and neuronal loss. Although amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau remain central pathological hallmarks, interconnected mechanisms contribute to disease progression and limit the effectiveness of single-target therapies. Current small-molecule drugs mainly provide symptomatic relief, whereas recently approved monoclonal antibodies have broadened the therapeutic landscape but still show modest clinical benefits, high treatment costs, and relevant safety concerns. GPR40/FFAR1, a transmembrane lipid-sensing G protein-coupled receptor, has emerged as a promising target because its activation may modulate neurotrophic signaling, neurogenesis, inflammatory regulation, neuronal survival, mitochondrial protection, autophagy, and synaptic plasticity. Preclinical studies suggest that GPR40/FFAR1 activation improves cognitive performance and attenuates AD-related pathological events through CREB activation, increased neurotrophic factor expression, reduced oxidative stress, restoration of autophagic flux, and inhibition of neuroinflammatory pathways, including NLRP3 inflammasome signaling. This review discusses the biological basis, pharmacological evidence, and medicinal chemistry advances supporting GPR40/FFAR1 as a potential therapeutic target for AD, while highlighting translational challenges related to selectivity, brain penetration, long-term safety, and target engagement.},
}

@article {pmid42836668,
year = {2026},
author = {Aboseif, A and Cacciaguerra, L and Vilaseca, A and Kondrakunta, S and Paramasivan, NK and Stabile, A and Patil, A and Li, X and Sarker, P and Christenson, LR and Brinkmann, B and Schwarz, CG and Kantarci, K and McKeon, A and Zekeridou, A and Basso, MR and Wingerchuk, DM and Irani, SR and Pittock, SJ and Zeydan, B and Dubey, D},
title = {Selective Limbic and Striatal Atrophy Corresponds to Regional Gene Expression in Leucine-Rich Glioma-Inactivated-1 Immunoglobulin G Autoimmune Encephalitis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78389},
pmid = {42836668},
issn = {1531-8249},
abstract = {OBJECTIVE: To characterize regional brain atrophy patterns, evaluate their association with regional leucine-rich glioma-inactivated-1 (LGI1) gene expression, and identify clinical predictors of hippocampal atrophy in LGI1 autoimmune encephalitis (AE).

METHODS: This study compared regional brain volumes in LGI1-AE patients versus age- and sex-matched healthy controls (HC) and Alzheimer's disease (AD) patients. LGI1 gene expression was derived from the Allen Human Brain Atlas. Multivariable linear regression and generalized linear models were utilized.

RESULTS: A total of 55 LGI1-AE patients were included. Median age was 68 years (IQR 62.5-74.2 years) at volumetric analysis, after 19 months (IQR 11-45 months) from symptom onset. Compared with HC (n = 55) and AD patients (n = 55), LGI1-AE patients had greater regional atrophy of the hippocampus, insula, caudate, and putamen (p < 0.002). Longitudinal analyses demonstrated hippocampal and pallidal atrophy after covariate adjustment. Among those who did not fulfill limbic encephalitis criteria and/or had non-lesional magnetic resonance imaging, limbic and striatal atrophy were identified compared with HC (p < 0.01). Regions with the greatest differential atrophy corresponded to higher LGI1 gene expression (Spearman ρ = 0.7, p = 0.005). Severe cognitive deficits at diagnosis (β = -0.56; p = 0.002) and longer disease duration (β = -0.01; p = 0.001) independently predicted total hippocampal volume (R[2] = 0.31).

INTERPRETATION: LGI1-AE demonstrates a distinct pattern of limbic and striatal atrophy that differs from AD and aligns with regional LGI1 expression, supporting a model of selective network vulnerability. Greater baseline cognitive impairment and longer disease duration independently associated with hippocampal atrophy, underscoring the potential importance of early diagnosis and treatment to limit structural brain injury. ANN NEUROL 2026.},
}

@article {pmid42836738,
year = {2026},
author = {Sahelijo, N and Rajagopalan, P and Qian, L and Rahman, R and Goldstein, D and Thomopoulos, SI and Bennett, DA and Farrer, LA and Stein, TD and Shen, L and Huang, H and Nho, K and Saykin, AJ and Davatzikos, C and Thompson, PM and Tcw, J and Jun, GR},
title = {Cell-based polygenic risk scores predict clinical progression and prioritize network-based therapeutic targets in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {10},
pages = {e71895},
pmid = {42836738},
issn = {1552-5279},
support = {/AG/NIA NIH HHS/United States ; R01-AG069453//National Institutes of Health (NIH)/ ; R01-AG082046//National Institutes of Health (NIH)/ ; U01-AG068057//National Institutes of Health (NIH)/ ; U01-AG082665//National Institutes of Health (NIH)/ ; U19-AG079774//National Institutes of Health (NIH)/ ; P30-AG072978//National Institutes of Health (NIH)/ ; U19-AG068753//National Institutes of Health (NIH)/ ; R01-AG082362//National Institutes of Health (NIH)/ ; R01-AG083941//National Institutes of Health (NIH)/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; Genetic Risk Score ; Disease Progression ; Female ; Apolipoproteins E/genetics ; Male ; Aged ; Astrocytes/metabolism ; Induced Pluripotent Stem Cells ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND: Late-onset Alzheimer's disease (AD) exhibits substantial biological heterogeneity. We developed a framework linking cell-type-specific polygenic risk profiles to precision medicine in AD.

METHODS: Cell-based polygenic risk scores (cbPRSs) derived from single-nucleus RNA-seq co-expression networks were evaluated in Alzheimer's Disease Neuroimaging Initiative (ADNI) and Framingham Heart Study (FHS) cohorts. Network hubs were prioritized using a graph-based PageRank algorithm and candidate drugs were validated in human-induced pluripotent stem cell (hiPSC)-derived astrocytes.

RESULTS: Cell-based PRS analysis identified two genetic risk axes independent of network cell-type labels: an apolipoprotein E (APOE)-concentrated axis (Ast-M2/Oli-M45) and an APOE-independent axis (Ast-M10/Oli-M50), which predicted accelerated progression to AD (hazard ratio: 1.25-2.02) and correlated with localized temporal lobe atrophy, reduced glucose metabolism, and global amyloid burden. High-risk status specifically upregulated complement C4a protein expression in postmortem brains. PageRank network analysis identified four candidate drugs targeting the APOE-containing astrocyte network. Experimental treatment with estradiol and levetiracetam significantly reduced APOE and complement C4 gene expression in hiPSC-derived astrocytes.

DISCUSSION: By integrating cell-based genetic risk with network-level target prioritization, this framework enables robust patient stratification and experimental target validation.},
}

Humans
*Alzheimer Disease/genetics/pathology
Genetic Risk Score
Disease Progression
Female
Apolipoproteins E/genetics
Male
Aged
Astrocytes/metabolism
Induced Pluripotent Stem Cells
Genetic Predisposition to Disease

@article {pmid42837119,
year = {2026},
author = {Klachacz, A and Malik, A},
title = {[Potential role of CHI3L1 in ischemic stroke - a neuroinflammatory or neuroprotective factor?].},
journal = {Postepy biochemii},
volume = {72},
number = {3},
pages = {201-210},
doi = {10.18388/wht2rw10},
pmid = {42837119},
issn = {0032-5422},
mesh = {Humans ; *Chitinase-3-Like Protein 1/metabolism/physiology ; Animals ; *Ischemic Stroke/metabolism/physiopathology ; Neuroprotective Agents/metabolism ; Signal Transduction ; *Brain Ischemia/metabolism ; *Neuroinflammatory Diseases/metabolism ; *Stroke/metabolism ; },
abstract = {Ischemic stroke is one of the leading causes of disability and death among adults worldwide. It occurs when blood flow to the brain is interrupted. Currently available treatments for patients with ischemic stroke focus solely on restoring blood flow. Therefore, there is a lack of methods that would accelerate brain regeneration after a stroke or even provide a protective effect. This study describes the role of the astrocyte-secreted protein CHI3L1 (chitinase-3-like protein 1) in the pathophysiology of stroke, as well as other diseases of the central nervous system. The structure of the protein, the receptors to which CHI3L1 binds and the activated signaling pathways along with the resulting biological effects relevant to ischemic stroke are discussed. It is indicated that changes in CHI3L1 levels potentially influence post-stroke regeneration in both humans and animal models. The common mechanisms of CHI3L1 action across various neurological diseases suggest its significant role in the future diagnosis and treatment of ischemic stroke, Alzheimer’s and Parkinson’s diseases, and glioma.},
}

Humans
*Chitinase-3-Like Protein 1/metabolism/physiology
Animals
*Ischemic Stroke/metabolism/physiopathology
Neuroprotective Agents/metabolism
Signal Transduction
*Brain Ischemia/metabolism
*Neuroinflammatory Diseases/metabolism
*Stroke/metabolism

@article {pmid42824090,
year = {2026},
author = {Schwartz, NU and Ellingson, T and Nguyen, H and Lin, Z and Ashton, NJ and Dage, JL and Deniz, K and Dietz, CD and Ljubenkov, PA and Miller, BL and Nael, K and Possin, K and Rojas, JC and Rosen, HJ and Saloner, R and Soleimani-Meigooni, DN and Staffaroni, AM and Stephens, ML and Tammewar, G and Wang, Y and La Joie, R and Rabinovici, GD and Boxer, AL and VandeVrede, L},
title = {Evaluation of plasma neurofilament and glial fibrillary acidic protein to predict or detect amyloid related imaging abnormalities.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70446},
pmid = {42824090},
issn = {2352-8729},
support = {K23 AG073514/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; T32 AG023481/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: Amyloid-targeting therapies (ATT) require frequent magnetic resonance imaging monitoring to detect vasogenic edema and hemorrhage, i.e., amyloid-related imaging abnormalities (ARIA). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are potential blood-based biomarkers (BBM) of ARIA.

METHODS: Plasma NfL and GFAP were longitudinally collected in an ATT clinic and natural log transformed. Baseline, pre-ARIA, and trajectories were compared between patients with (N = 15) and without (N = 45) ARIA.

RESULTS: Baseline NfL and GFAP did not differ between patients with or without ARIA (ln[NfL] ECLIA 1.24 ± 0.38 pg/mL vs 1.25 ± 0.40 pg/mL, p = 0.77; ln[NfL] Simoa 2.87 ± 0.47 pg/mL vs 2.98 ± 0.40 pg/mL, p = 0.30, ln[GFAP] ECLIA 4.95 ± 0.36 pg/mL vs 4.88 ± 0.47 pg/mL, p = 0.69). No significant changes were seen at the timepoint preceding ARIA, and ARIA incidence made no detectable impact on biomarker trajectories.

DISCUSSION: Biobanking in treatment clinics can evaluate clinical utility of BBMs as monitoring tools. These findings do not support a strong association between NfL or GFAP and ARIA in the ATT clinic.},
}

@article {pmid42825454,
year = {2026},
author = {Varshney, H and Siddique, YH},
title = {Molecular and genetic basis of alzheimer's disease and emerging treatment Modalities.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-21},
doi = {10.1080/17582024.2026.2739332},
pmid = {42825454},
issn = {1758-2032},
abstract = {BACKGROUND: Alzheimer's disease (AD) is linked to various causes and pathological processes. It represents a major global health challenge due to its increasing prevalence in aging populations. AD involves multifactorial pathological mechanisms. Two different forms of AD defined by changes in specific genes like APOE4, CLU, TREM2, PICALM, BIN1, MS4A, CR1, ABCA7 and APH1B. Apart from specific genetic mutations, there are multiple risk factors such as aging, obesity, lifestyle, head injury, drinking, smoking and environmental factors that further influence disease risk and its progression.

METHODS: The literature of this review article was taken from different search engines viz. Pubmed, Google Scholar and Scopus, explaining modifiable contributing factors and prognostic markers, including the genetics of AD and overall, this review analyzes literature published between 2000 to 2025 to summarizes the current status of disease, highlighting its importance for improving diagnosis, prognosis, and the development of targeted therapeutic strategies.

RESULT: There are multiple contributing factors in both the disease mechanism and development of AD, apart from amyloid hypothesis and neurofibrillary tangles.

DISCUSSION: A strategic analysis and targeted treatment of these contributing factors could help mitigate the progression of AD and offer potential protective benefits.},
}

@article {pmid42825521,
year = {2026},
author = {Nicol, NI and Li, T and Su, Q and Suhocki, A and Dunlap, E and Zhou, X and Jester, HM and Swift, NA and Underwood, E and Lee, J and Cervera-Juanes, R and Ma, T},
title = {AMPK Activator MK-8722 Improves Spatial Memory Deficit and Alters Metabolome in APP/PS1 AD Mouse Model.},
journal = {Journal of neurochemistry},
volume = {170},
number = {10},
pages = {e70563},
doi = {10.1111/jnc.70563},
pmid = {42825521},
issn = {1471-4159},
support = {R01 AG073823/AG/NIA NIH HHS/United States ; R01 AG082388/AG/NIA NIH HHS/United States ; RF1 AG082388/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Metabolome/drug effects/physiology ; Mice ; Mice, Transgenic ; *AMP-Activated Protein Kinases/metabolism ; Presenilin-1/genetics ; *Amyloid beta-Protein Precursor/genetics ; *Memory Disorders/drug therapy/metabolism/genetics ; Disease Models, Animal ; Male ; Hippocampus/drug effects/metabolism ; *Spatial Memory/drug effects/physiology ; },
abstract = {Alzheimer's disease (AD) involves early synaptic vulnerability and systemic metabolic dysfunction, yet the impact of peripheral metabolic state on brain function remains unclear. Previous studies indicate a link between AMP-activated protein kinase (AMPK) signaling dysregulation and AD pathophysiology. Here we tested whether systemic treatment of a potent pan-AMPK activator MK-8722 influences cognitive function, synaptic plasticity, and circulating metabolic profiles in APP/PS1 AD model mice at the age of 6-8 months. MK-8722 was well tolerated and activated AMPK in the liver but not in the hippocampus. Our findings revealed that MK-8722 selectively improved AD-associated hippocampal-dependent spatial memory deficits and enhanced dendritic spine maturation in the hippocampus of APP/PS1 mice. In contrast, MK-8722 did not alter hippocampal long-term potentiation (LTP). In-depth analysis of plasma lipidomics and metabolomics revealed coordinated disruptions in glycerophosphatidylcholine species, glutathione cycling, carnitine-dependent fatty acid transport, and the kynurenine pathway in APP/PS1 mice, which were partially normalized by MK-8722 treatment. These findings suggest that peripheral AMPK activation can remodel systemic metabolic networks and improve certain aspects of cognitive and synaptic outcomes in early AD, supporting a model in which metabolic interventions outside the brain influence neuronal resilience.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/genetics
*Metabolome/drug effects/physiology
Mice
Mice, Transgenic
*AMP-Activated Protein Kinases/metabolism
Presenilin-1/genetics
*Amyloid beta-Protein Precursor/genetics
*Memory Disorders/drug therapy/metabolism/genetics
Disease Models, Animal
Male
Hippocampus/drug effects/metabolism
*Spatial Memory/drug effects/physiology

@article {pmid42825842,
year = {2026},
author = {Martinez Holst, MA and Sierra Valiente, AM and Garcia-Becerra, CA},
title = {Incidence, severity, and associated risk factors for amyloid-related imaging abnormalities in anti-amyloid monoclonal antibody therapy for early Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {10},
pages = {},
pmid = {42825842},
issn = {1590-3478},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/epidemiology/genetics ; *Amyloid beta-Peptides ; *Antibodies, Monoclonal/therapeutic use ; Incidence ; Risk Factors ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are the most concerning side effect of the treatment for early Alzheimer's disease (AD) with anti-amyloid monoclonal antibodies (mAbs).

OBJECTIVE: This study systematically evaluates the incidence, severity, and associated risk factors of ARIA in patients with early AD receiving anti-amyloid mAbs therapy.

METHODS: A comprehensive systematic review and meta-analysis were conducted following PRISMA guidelines. Assessed outcomes included ARIA incidence, symptomatic cases and severity, radiographic severity, and risk factors. Pooled incidences and odds ratios were estimated with a random effects model using the R software (version 4.5.2).

RESULTS: The systematic search yielded a total of 20 articles, representing 21 phase 3 randomized controlled trials that involved 12,610 AD patients. Pooled incidence was 5.4% for ARIA-E and 10.27% for ARIA-H. Most cases being asymptomatic and radiographically mild to moderate. Risk factor analysis revealed that ApoE 4 homozygotes carriers (OR = 5.12), ApoE 4 heterozygotes carriers (OR = 1.91), higher mAb dosage (OR = 2.0) and baseline microhemorrhages (OR = 1.43) had a major influence on ARIA-E occurrence, as for ARIA-H incidence was higher in ApoE 4 heterozygous (OR = 1.65) and homozygotes carriers (OR = 4.65). Moreover, ApoE 4 heterozygous and homozygotic carriers were associated with symptomatic (OR = 1.52;3.68) and severe radiographic (OR = 2.11;6.31) ARIA-E.

DISCUSSION: ARIA remains a significant safety concern in anti-amyloid mAb therapy, with incidence and severity influenced by genetic, neuroimaging, and treatment-related factors. Future research should focus on refining risk stratification and understanding long-term consequences of ARIA.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/epidemiology/genetics
*Amyloid beta-Peptides
*Antibodies, Monoclonal/therapeutic use
Incidence
Risk Factors

@article {pmid42826598,
year = {2026},
author = {Rava, A and Di Trapano, M and Tse, C and Ji, L and Bid, HK and Trezza, V},
title = {Acidic cannabinoids in brain disorders: Neurobiological mechanisms, preclinical evidence, and translational challenges.},
journal = {Neuroscience and biobehavioral reviews},
volume = {191},
number = {},
pages = {107005},
doi = {10.1016/j.neubiorev.2026.107005},
pmid = {42826598},
issn = {1873-7528},
abstract = {Acidic cannabinoids, including tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and related biosynthetic precursors, represent the predominant phytocannabinoid forms naturally produced by Cannabis sativa. Long considered pharmacologically inactive intermediates, these compounds are now increasingly recognized as bioactive molecules with potential therapeutic relevance for brain disorders. Compared with their decarboxylated counterparts, acidic cannabinoids exhibit distinct physicochemical, pharmacokinetic, and pharmacodynamic properties that may confer reduced psychotropic liability together with unique neurobiological effects. Emerging preclinical evidence indicates that acidic cannabinoids modulate multiple processes implicated in neurological and psychiatric disorders, including serotonergic and endocannabinoid signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, calcium dyshomeostasis, and synaptic transmission. In this review, we critically examine current knowledge regarding acidic cannabinoids in the context of brain disorders. We first summarize their biosynthesis, chemical stability, pharmacokinetic characteristics, and pharmacological differences from neutral cannabinoids. We then examine preclinical evidence supporting their potential therapeutic effects in epilepsy, anxiety, depression, psychosis-related conditions, and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. We also discuss how artificial intelligence and computational approaches may support target identification, formulation optimization, pharmacokinetic modeling, and the development of personalized cannabinoid-based interventions. Finally, we highlight key methodological and translational challenges limiting the field and outline priorities for future research. Overall, acidic cannabinoids emerge as promising but still underexplored multitarget compounds with potential relevance for the treatment of brain disorders.},
}

@article {pmid42826681,
year = {2026},
author = {Xu, F and Li, H and Yan, Y and Chen, L and Sheng, Z and Dou, B and Yan, C and Zhu, X and Xu, Y},
title = {Cyclic nucleotide signaling through phosphodiesterase 1 inhibition and its interaction with the competing endogenous RNA network regulates cognition.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {204},
number = {},
pages = {119963},
doi = {10.1016/j.biopha.2026.119963},
pmid = {42826681},
issn = {1950-6007},
abstract = {BACKGROUND: Phosphodiesterase 1 (PDE1) has been demonstrated to be a potential drug target for a variety of diseases, ranging from peripheral system disease (PSD) to central nervous system disorders (CNSD). However, how cyclic nucleotide signaling, regulated by PDE1, particularly its isoform PDE1A, regulates the pathology of neurodegenerative disorders, including Alzheimer's disease (AD), remains unclarified.

METHOD: The Gene Expression Omnibus (GEO) database, a public gene expression repository, was used to analyze the role of PDE1 dysfunction in AD pathology. The mRNA and long non-coding RNA (lncRNA) were analyzed by comparing their differences in the GENCODE data resource V22. The relationship between PDE1, particularly PDE1A, and competing endogenous RNA (ceRNA) was validated by a dual-luciferase assay and reverse transcription-quantitative PCR (RT-qPCR), suggesting a potential ceRNA relationship among XIST, miR-338-3p, and PDE1A. Further cell-based assay and behavioral tests were conducted to determine the neuroprotective and memory-enhancing effects of PDE1 inhibition in cell and mouse models of AD.

RESULTS: A total of 11,781 differentially expressed genes (DEGs) were identified as AD- related genes. Approximately 1131 genes were identified as mitochondrial dysfunction-related by Venn plot analysis and were closely associated with AD pathology. PDE1, especially PDE1A, interacts with the lncRNA-microRNA network to promote cellular infiltration. These bioinformatic analyses were further supported by cell-based assays and behavioral studies, which demonstrated that treatment with the PDE1 inhibitor vinpocetine and PDE1A knockout ameliorated mitochondrial morphological abnormalities, restored immune function, and enhanced memory in a mouse model of AD.

CONCLUSION: These findings demonstrate that PDE1, particularly PDE1A activity, plays critical roles in AD progression by modulating mitochondrial morphology, immunity, and neuronal function, ultimately contributing to cognitive deficits.},
}

@article {pmid42828019,
year = {2026},
author = {Kucukbagriacik, Y and Saribas, GS and Ates, K and Ozturk, C and Kahyaoglu, E and Kislal, S and Akgul, CC and Karacalioglu, AO and Goksoy, C and Kantarcioglu, M},
title = {Exploratory effects of coffee-derived exosome-like nanoparticles in a fibrillar amyloid-beta 1-42-induced neurodegenerative rat model: evidence from fluorodeoxyglucose positron emission tomography and phosphorylated tau/amyloid precursor protein expression.},
journal = {PeerJ},
volume = {14},
number = {},
pages = {e21739},
pmid = {42828019},
issn = {2167-8359},
mesh = {Animals ; Male ; *Amyloid beta-Peptides/metabolism ; Rats, Sprague-Dawley ; *tau Proteins/metabolism ; *Nanoparticles/chemistry/administration & dosage ; *Exosomes/chemistry ; Peptide Fragments ; Rats ; Phosphorylation ; Disease Models, Animal ; *Coffee/chemistry ; Fluorodeoxyglucose F18 ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta 1-42 (Aβ1-42) accumulation, tau pathology, and metabolic dysfunction. This exploratory study evaluated the effects of coffee-derived exosome-like nanoparticles (CELNs) on selected metabolic and histopathological endpoints in a fibrillar Aβ1-42-induced neurodegenerative rat model.

METHODS: Fifty male Sprague-Dawley rats were randomly divided into five groups (N = 10 each): Control (C), sham (SF), a fibrillar Aβ1-42-induced neurodegenerative rat model (AD), AD treated with a low dose of CELNs (AD + LE, 10 mg/kg/day), and AD treated with a high dose of CELNs (AD + HE, 20 mg/kg/day) for 14 days. CELNs were quantified and characterized using the bicinchoninic acid method, scanning electron microscopy, and nanoparticle tracking analysis (NTA). Micro-positron emission tomography/computed tomography fluorodeoxyglucose (MicroPET/CT FDG) imaging of the central nervous system was performed in all groups at the end of treatment. Subsequently, all animals were sacrificed, and hippocampal tissues were subjected to histopathological analysis.

RESULTS: MicroPET imaging demonstrated a significant, dose-dependent increase in cerebral glucose metabolism in AD rats treated with CELNs compared with the untreated AD group. Histopathological evaluations were consistent with the imaging data: in AD groups receiving CELNs, phospho-tau and beta-amyloid precursor protein expression were significantly reduced in the hippocampal cornu ammonis 2 (CA2) and dentate gyrus regions compared with the untreated AD group.

CONCLUSIONS: In this exploratory fibrillar Aβ1-42-induced neurodegenerative rat model, oral CELN administration was associated with dose-dependent partial improvements in cerebral glucose metabolism and region-specific reductions in hippocampal phosphorylated tau (p-Tau) and amyloid precursor protein (APP) immunoreactivity. However, these are preliminary biomarker-level findings that support further investigation of CELNs; definitive confirmation of functional and cognitive benefits requires additional behavioral, biodistribution, and experimental validation.},
}

Animals
Male
*Amyloid beta-Peptides/metabolism
Rats, Sprague-Dawley
*tau Proteins/metabolism
*Nanoparticles/chemistry/administration & dosage
*Exosomes/chemistry
Peptide Fragments
Rats
Phosphorylation
Disease Models, Animal
*Coffee/chemistry
Fluorodeoxyglucose F18
*Alzheimer Disease/drug therapy/diagnostic imaging/metabolism
*Amyloid beta-Protein Precursor/metabolism
Positron-Emission Tomography

@article {pmid42828568,
year = {2026},
author = {Bernetti, C and Calandrelli, R and Pilato, F and Di Lazzaro, V and Zobel, BB and D'Amelio, M and Mallio, CA},
title = {Exploring the role of glymphatic system in Alzheimer's disease with insights from MRI-based studies: a systematic review.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42828568},
issn = {1432-1920},
abstract = {BACKGROUND: The glymphatic constitutes a crucial neurophysiological mechanism for the clearance of interstitial solutes and neurotoxic metabolites from the central nervous system. Dysfunction within this pathway is increasingly implicated in the etiopathogenesis of neurodegenerative diseases, notably Alzheimer's disease (AD). Advanced magnetic resonance imaging (MRI) modalities, such as diffusion tensor image analysis along the perivascular space (DTI-ALPS), have emerged as non-invasive, in vivo approaches quantifying glymphatic transport efficacy and its association with cognitive decline and AD progression.

METHODS: This systematic review was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. and systematic literature retrieval was executed across PubMed, Cochrane, and Scopus databases, targeting studies that employed MRI-based metrics to assess glymphatic functionality in the context of AD.

RESULTS: A total of 35 studies fulfilled the inclusion criteria. AD patients exhibited significantly reduced DTI-ALPS indices, correlating with elevated enlarged perivascular space (ePVS) volumes, neurocognitive deterioration, and cerebral atrophy. Notably ePVSs enlargement emerged as a surrogate marker of glymphatic dysfunction and a predictor of MCI-to-AD conversion. However, amyloid PET correlations exhibited inter-study heterogeneity.

CONCLUSIONS: MRI derived biomarkers, particularly DTI-ALPS index and ePVSs analysis, demonstrate high potential as surrogate indicators of glymphatic impairment in AD. These findings underscore their diagnostic and prognostic value, warranting harmonization of imaging protocols and longitudinal investigations to establish their translational utility in clinical biomarker frameworks.

CLINICAL RELEVANCE STATEMENT: MRI biomarkers of glymphatic dysfunction provide valuable insights into Alzheimer's disease pathophysiology and progression. These imaging markers may enhance early diagnosis, monitor disease progression, and evaluate treatment efficacy in AD.},
}

@article {pmid42828605,
year = {2026},
author = {Przywara, D and Petniak, A and Gil-Kulik, P},
title = {The Therapeutic Potential of MicroRNAs Delivered By Mesenchymal Stem Cells in Parkinson's Disease, Alzheimer's Disease, and Stroke: A Systematic Review of Preclinical Studies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42828605},
issn = {1559-1182},
mesh = {*MicroRNAs/administration & dosage/genetics/therapeutic use ; Animals ; Humans ; *Alzheimer Disease/therapy/genetics ; *Stroke/therapy/genetics ; *Mesenchymal Stem Cells/metabolism ; *Mesenchymal Stem Cell Transplantation/methods ; *Parkinson Disease/therapy/genetics ; },
abstract = {Population aging has led to a substantial increase in the prevalence of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and stroke. As current therapeutic strategies are largely limited to symptomatic management, the identification of disease-modifying treatments remains a major unmet clinical need. Mesenchymal stem cells (MSCs) and MSCs-derived microRNAs (miRNAs) have emerged as promising therapeutic candidates for these conditions. A systematic literature search was conducted in the PubMed and Scopus databases in accordance with the PRISMA guidelines. The aim was to synthesize the available evidence regarding the effects of MSCs-derived miRNAs on cellular processes, including apoptosis, proliferation, inflammation, oxidative stress, and motor function in experimental models of PD, AD, and stroke. Risk of bias was assessed using the SYRCLE Risk of Bias tool for animal intervention studies and the modified OHAT Risk of Bias Rating Tool (mOHAT). A total of 37 preclinical studies were included in the review: 9 focused on PD, 10 on AD, and 18 on stroke. The synthesized evidence indicates that specific MSCs-derived miRNAs, particularly miR-133b, miR-146a, miR-17-92, and miR-223, exert significant neuroprotective effects. These miRNAs actively modulate gene expression, attenuate neuroinflammation and apoptosis, and reduce the accumulation of disease-specific pathological markers, including α-synuclein and amyloid-β (Aβ). Furthermore, targeted delivery of these miRNAs was associated with improved motor and cognitive outcomes across the evaluated animal models. MSCs-derived miRNAs demonstrate considerable therapeutic potential for the treatment of neurodegenerative diseases and stroke through the modulation of multiple pathological pathways. However, as the current evidence is derived exclusively from in vitro and animal studies, future research should focus on the development of safe, standardized, and reproducible protocols to facilitate the translation of these findings into human clinical trials. The review was registered in the Open Science Framework (OSF): https://osf.io/cxt9b .},
}

*MicroRNAs/administration & dosage/genetics/therapeutic use
Animals
Humans
*Alzheimer Disease/therapy/genetics
*Stroke/therapy/genetics
*Mesenchymal Stem Cells/metabolism
*Mesenchymal Stem Cell Transplantation/methods
*Parkinson Disease/therapy/genetics

@article {pmid42828695,
year = {2026},
author = {Inui, Y and Takechi, H and Watanabe, H and Kato, T and Ito, K and Kobayashi, R and Toyama, H and Inoue, M},
title = {Multimodal neuroimaging in dementia and neurodegenerative disorders: complementary roles of clinically available nuclear medicine and MRI in the era of disease-modifying therapies.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42828695},
issn = {1867-108X},
abstract = {The introduction of anti-amyloid-β antibody therapies has fundamentally changed the clinical landscape of dementia, shifting the role of neuroimaging from diagnosis toward therapeutic decision-making. Amyloid positron emission tomography (PET) has become essential for confirming amyloid pathology and determining treatment eligibility. However, amyloid deposition is frequently observed in cognitively normal elderly individuals and in non-Alzheimer neurodegenerative disorders, indicating that amyloid status alone is insufficient to explain clinical symptoms. In this context, imaging modalities reflecting neurodegeneration, including structural magnetic resonance imaging (MRI) and functional imaging such as [18]F-FDG-PET and brain perfusion single-photon emission computed tomography (SPECT), remain important for assessing disease severity and functional impairment. Furthermore, discrepancies between imaging biomarkers-such as the presence of neurodegeneration without amyloid pathology in cases clinically suspected of Alzheimer's disease, and atypical imaging patterns-are commonly encountered in clinical practice and may reflect underlying pathological heterogeneity. A multimodal imaging approach that integrates multiple biomarkers provides complementary information and may improve diagnostic accuracy and clinical interpretation. In addition, other imaging modalities, including dopamine transporter (DAT) imaging and cardiac sympathetic imaging, can contribute to the evaluation of non-Alzheimer pathologies. This review summarizes the current roles of clinically available multimodal imaging in dementia, with a focus on nuclear medicine and MRI, highlighting their complementary value and clinical implications in the era of disease-modifying therapies.},
}

@article {pmid42828701,
year = {2026},
author = {Lei, Y and Luo, Y and Li, L},
title = {Collagen Triple Helix Repeat Containing 1 (CTHRC1) in the Nervous System: Expression, Signaling Mechanisms, and Functional Implications.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {4},
pages = {},
pmid = {42828701},
issn = {1559-1166},
support = {2024AAC03777//Natural Science Foundation of Ningxia Province/ ; },
mesh = {Animals ; Humans ; *Extracellular Matrix Proteins/metabolism/genetics ; *Signal Transduction ; },
abstract = {Collagen triple helix repeat containing 1 (CTHRC1) is a secreted extracellular matrix (ECM)-associated protein involved in tissue remodeling, fibrosis, and cancer, but its functions in the nervous system remain incompletely defined. Evidence from peripheral nerve, brain tumor, neurodegeneration, and regeneration models suggests that CTHRC1 may exert context-dependent effects across neural and stromal cell populations. In Schwann cells, CTHRC1 regulates proliferation, migration, and the timing of myelination, whereas in glioma it promotes invasive behavior and treatment-resistant phenotypes. Human cortical proteomics, mouse-model studies, systems genetics, and a neuronal cell model associate CTHRC1 with Alzheimer's disease-related phenotypes, although bulk tissue does not identify the cellular source and a small cerebrospinal fluid cohort showed no significant change. Temporally resolved single-cell analysis in zebrafish identified a transient cthrc1a-expressing fibroblast state required for coordinated inflammatory dynamics during regeneration; an equivalent mammalian mechanism has not been established. Evidence connecting CTHRC1 to synaptic regulation, neuroprotection, Parkinson's disease, and cerebrovascular repair is still preliminary. Wnt, TGF-β/Smad, PI3K/AKT, and MAPK/ERK pathways provide candidate mechanisms, but many were characterized outside normal neural cells. This review critically evaluates the evidence by model and cell type and discusses biomarker and therapeutic prospects, including delivery, specificity, and safety constraints.},
}

Animals
Humans
*Extracellular Matrix Proteins/metabolism/genetics
*Signal Transduction

@article {pmid42830424,
year = {2026},
author = {Chen, Y and Liu, Y and Xie, J and Wang, S and Zhou, D and Song, G and Dou, Y},
title = {A LIFU-responsive phase-change nanoplatform enhances hippocampal galantamine exposure and cognitive outcomes in APP/PS1 mice.},
journal = {Journal of biomaterials science. Polymer edition},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/09205063.2026.2741654},
pmid = {42830424},
issn = {1568-5624},
abstract = {Alzheimer's disease (AD) lacks spatiotemporally controllable strategies for drug delivery to deep brain targets. Galantamine (GTM) is clinically used for symptomatic management of AD, yet systemic dosing is constrained by peripheral adverse effects and limited, nonselective brain exposure. Here, we engineered a PEGylated phase-change liposomal nanoplatform co-loading GTM and perfluoropentane (PFP) (PEG-LIP@PFP@GTM) to integrate noninvasive nose-to-brain delivery with low-intensity focused ultrasound (LIFU)-assisted enhancement of GTM exposure in the hippocampal region. PEG-LIP@PFP@GTM showed a hydrodynamic diameter of 158.8 ± 1.6 nm with a PDI of 0.165 ± 0.017, an encapsulation efficiency of 69.26 ± 2.07%, and a drug loading content of 6.37 ± 0.65%. PFP endowed the formulation with thermo-responsive phase-transition behavior and LIFU-enhanced GTM release under physiological-temperature conditions. In vivo fluorescence imaging and ex vivo brain sectioning provided evidence of brain accessibility after intranasal administration, while also identifying 4 h post-dosing as a practical window for hippocampal LIFU irradiation. In APP/PS1 mice, compared with the non-irradiated nanoplatform group, phase-change liposomes combined with hippocampal LIFU irradiation significantly increased PSD95 fluorescence intensity (p = 0.0028) and improved Y-maze novel-arm time (p = 0.0003) and Morris water maze target-quadrant time (p = 0.0237), and significantly reduced the Aβ-positive area (p = 0.0461). Histological examination revealed no overt abnormalities in the nasal mucosa or major peripheral organs under the tested conditions. Collectively, these findings support combining intranasal nanocarrier delivery with externally applied hippocampal LIFU, with LIFU activation providing additional benefit beyond non-irradiated nanocarrier treatment under the tested conditions.},
}

@article {pmid42818885,
year = {2026},
author = {Kuik, EJ and Baena-Tan, C and Moriguchi, S and Braga, J and Miler, L and Rusjan, P and Bagby, M and Husain, MI and Vasdev, N and Tomoda, T and Banasr, M and Kloiber, S and Meyer, JH},
title = {Effects of sex, treatment resistance, and antidepressant treatment on monoamine oxidase B total distribution volume.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {42818885},
abstract = {Monoamine oxidase B (MAO-B) is a high-density protein located mainly in astrocytes that influences mitochondrial function and transition to astrogliosis. MAO-B produces hydrogen peroxide while metabolizing non-serotonergic monoamines. Elevated MAO-B level is implicated in the pathophysiology of several common neuropsychiatric diseases. The aims are to examine the effect of treatment resistant major depressive episodes, sex, and antidepressant treatment on MAO-B total distribution volume ([ [11] C]SL25.1188 V T), index of MAO-B level. [ [11] C]SL25.1188 PET was applied in 95 adults (29 with MDE and no history of treatment-resistance (NTR-MDE), 26 with MDE and history of treatment-resistance (TRD), and 40 healthy control (HC)). A subset of NTR-MDE and TRD (n=13) were scanned before and after treatment with phenelzine, rasagiline, or duloxetine. [ [11] C]SL25.1188 V T was higher in grey matter regions in females (10%, p <.001). [ [11] C]SL25.1188 V T was also higher in prefrontal cortex in TRD compared to HC (23%, p<.001) and TRD compared to NTR-MDE (6%, p =.033). Duloxetine had minimal effect on [ [11] C]SL25.1188 V T , but occupancy of rasagiline and phenelzine was ∼94%. This study discovered sex differences in MAO-B level, which may explain sex differences in prevalence or trajectory of illnesses with greater MAO-B level like Alzheimer's disease, traumatic brain injury and major depressive disorder. Given our findings of greater MAO-B level in prefrontal cortex of TRD and its insensitivity to serotonin reuptake inhibition, combined with potential harm of highly elevated MAO-B level, development of MAO-B inhibitors could be considered for a subset of TRD. Rasagiline and phenelzine demonstrate similarly potent occupancy in vivo at clinical dosage.},
}

@article {pmid42818911,
year = {2026},
author = {Han, S and Liu, F and Wang, D and Song, G},
title = {Aildenafil citrate with superior PDE5 selectivity ameliorates cognitive and behavioral impairments in APP/PS1 Alzheimer's disease mice: a preclinical phenotypic study.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1933588},
pmid = {42818911},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) imposes a significant global healthcare burden, and current available pharmacotherapies provide limited therapeutic benefits. Disrupted phosphodiesterase 5 (PDE5) signaling has been implicated in the pathogenesis of AD and other neurodegenerative disorders, positioning PDE5 inhibitors (PDE5Is) as a promising therapeutic strategy for AD treatment. This study evaluated the preclinical therapeutic potential of aildenafil citrate (AC), a selective PDE5I approved in China for the treatment of erectile dysfunction (ED), in AD treatment.

METHODS: Molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations were integrated to explore the molecular mechanisms of aildenafil. The APP/PS1 transgenic mouse model of AD was employed to assess the in vivo efficacy of AC through behavioral, pathological, and oxidative assessments.

RESULTS: In silico analyses indicated that aildenafil exhibited a higher predicted affinity through a strengthened electrostatic network anchored by key bidentate hydrogen bonds with Gln817 and enhanced π-π stacking interactions with Phe820. Behavioral assessments, including the Barnes maze and Open field tests, demonstrated that AC significantly ameliorates cognitive dysfunction and anxiety-like impairments. Pathological examinations revealed improved hippocampal morphology, upregulated neprilysin (NEP) expression, and reduced Aβ accumulation. The decreased malondialdehyde (MDA) levels further suggested a potential attenuation of systemic oxidative stress and provided preliminary support for further investigation into its effects on central redox status.

CONCLUSION: These findings offer an initial phenotypic characterization of AC in an AD mouse model, underscoring the need for comprehensive mechanistic studies to fully evaluate its potential as a repurposed AD therapeutic candidate.},
}

@article {pmid42821606,
year = {2026},
author = {Xu, MY and Bai, YD and Zeng, XQ and Tan, CR and Lai, YJ and Wang, YJ},
title = {Bazedoxifene restores myelin changes and attenuates cognitive deficits in a mouse model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490479},
doi = {10.1177/13872877261490479},
pmid = {42821606},
issn = {1875-8908},
abstract = {BackgroundDemyelination and remyelination are critical processes in the pathogenesis of Alzheimer's disease (AD). The selective estrogen receptor modulator bazedoxifene (BZA) has been shown to promote remyelination, suggesting its potential therapeutic efficacy.ObjectiveThis study aimed to evaluate the therapeutic efficacy of BZA in addressing demyelination and associated cognitive deficits in a mouse model of AD.MethodsThe changes in myelin and oligodendrocyte-related indicators in the brains of APP/PS1 mice were assessed via immunostaining. 5 × FAD transgenic mice received oral administration of BZA or vehicle for 3 months. The therapeutic outcomes were evaluated through behavioral tests, immunostaining and western blotting.ResultsAD mice exhibited pronounced myelin loss and oligodendrocytes depletion. BZA treatment attenuated cognitive decline, restored myelin changes and mitigated neurodegeneration in the brain. These effects were observed independently of alterations in amyloid-β deposition.ConclusionsThese findings provide compelling evidence supporting the involvement of demyelination in AD and suggest that BZA may represent a promising therapeutic agent for AD by targeting myelin repair mechanisms.},
}

@article {pmid42821845,
year = {2026},
author = {Shir, D and Algeciras-Schimnich, A and Piura, YD and Bornhorst, JA and Figdore, DJ and Elgenidi, A and Lachner, C and Graff-Radford, NR and Day, GS},
title = {Clinical Factors Associated With Discordant Plasma P-Tau217 and Established Alzheimer Disease Biomarkers.},
journal = {Neurology},
volume = {107},
number = {8},
pages = {e218591},
pmid = {42821845},
issn = {1526-632X},
support = {R01 AG041851/AG/NIA NIH HHS/United States ; RF1 AG069052/AG/NIA NIH HHS/United States ; R01 AG089380/AG/NIA NIH HHS/United States ; R01 AG075802/AG/NIA NIH HHS/United States ; UF1 NS125417/NS/NINDS NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R37 AG011378/AG/NIA NIH HHS/United States ; RF1 AG061900/AG/NIA NIH HHS/United States ; R01 AG056366/AG/NIA NIH HHS/United States ; UH2 AG083186/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; U01 NS120901/NS/NINDS NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/blood/diagnosis ; Female ; Biomarkers/blood ; Male ; Retrospective Studies ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid/blood ; Aged, 80 and over ; Middle Aged ; Phosphorylation ; Positron-Emission Tomography ; },
abstract = {BACKGROUND AND OBJECTIVES: Plasma phosphorylated tau (p-tau) 217 is increasingly used for Alzheimer disease (AD) diagnosis and treatment decisions but may be discordant with established AD biomarkers. False-positive (FP) plasma results may lead to overtreatment and false-negative (FN) results to missed or delayed disease-modifying therapies. We evaluated factors associated with discordant results.

METHODS: This retrospective study included participants enrolled in memory and aging studies at Mayo Clinic with "positive" (>0.324 pg/mL) or "negative" (<0.186 pg/mL) plasma p-tau217 results and confirmatory AD biomarkers. Plasma results were classified as true positive (TP), true negative (TN), FP, or FN, referencing amyloid-PET and CSF p-tau181/β-amyloid (Aβ) 42. Clinical and laboratory variables were compared using univariate analyses; multivariable logistic regression evaluated independent associations with discordance.

RESULTS: Among 706 participants (median 70.0 [interquartile range 15.8] years; 54% male), 60 (8.5%) had discordant plasma p-tau217 results. FN results (5.6%) were more frequent than FP results (2.8%; p = 0.007). Discordance was associated with older age (odds ratio [OR] 1.61 per decade, 95% CI 1.23-2.14) and obstructive sleep apnea (OR 1.94, 95% CI 1.08-3.49). FN (vs TP) results were associated with milder clinical stage (global Clinical Dementia Rating [CDR] ≤0.5 vs CDR ≥1; p < 0.001), higher Mini-Mental State Examination scores (OR 1.20 per point, 95% CI 1.05-1.36), obstructive sleep apnea (OR 2.01, 95% CI 1.01-4.3), higher body mass index (OR 1.11/kg/m[2], 95% CI 1.03-1.20), and higher estimated glomerular filtration rate (eGFR: OR 1.33/10 mL/min/1.73 m[2], 95% CI 1.05-1.69). In age-adjusted models, body mass index (OR 1.14, 95% CI 1.03-1.25), eGFR (OR 1.63/10 mL/min/1.73 m[2], 95% CI 1.22-2.16), and earlier clinical stage (CDR ≤0.5) were independently associated with FN results. FP (vs TN) results were associated with older age (OR 2.37, 95% CI 1.36-4.09), thyroid disease (OR 4.41, 95% CI 1.36-14.3), lower eGFR (OR 0.48/10 mL/min/1.73 m[2], 95% CI 0.31-0.66), and advanced disease stage (CDR ≥1). In age-adjusted models, eGFR (OR 0.54/10 mL/min/1.73 m[2], 95% CI 0.35-0.82) and advanced disease stage (CDR ≥ 1 vs CDR 0: OR 11.11, 95% CI 2.0-50.0; vs CDR 0.5: OR 4.55, 95% CI 1.12-16.67) were independently associated with FP results.

DISCUSSION: Plasma p-tau217 results and established AD biomarkers were discordant in 8.5% of participants. Clinical stage and factors related to brain amyloid clearance, renal clearance, and volume of distribution were associated with discordant results. These insights may inform mechanisms of discordance and identify patients requiring confirmatory biomarker measures.},
}

Humans
*tau Proteins/blood
*Alzheimer Disease/blood/diagnosis
Female
Biomarkers/blood
Male
Retrospective Studies
Aged
Amyloid beta-Peptides/cerebrospinal fluid/blood
Aged, 80 and over
Middle Aged
Phosphorylation
Positron-Emission Tomography

@article {pmid42824080,
year = {2026},
author = {Privšek, E and Marseglia, A and Košutić, I and Rosenberg, A and Granberg, T and Kramberger, MG and Kivipelto, M and Westman, E},
title = {Cerebral microbleed assessment on MRI in a memory clinic: Reliability, prevalence, and implications for anti-amyloid therapy.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {4},
pages = {e70472},
pmid = {42824080},
issn = {2352-8729},
abstract = {INTRODUCTION: Cerebral microbleeds (CMBs) represent an important magnetic resonance imaging (MRI) marker of cerebral small vessel pathology in memory-clinic populations, where vascular and neurodegenerative pathologies frequently overlap.

METHODS: This cross-sectional study included 747 patients from a Swedish memory clinic who underwent 3T MRI with susceptibility-weighted imaging. Two readers assessed CMBs using standardized criteria. Inter- and intra-observer agreement were evaluated before and after protocol refinement. CMB prevalence and burden were analyzed across diagnostic groups and by cerebrospinal fluid amyloid status.

RESULTS: CMBs were present in 28.6% of patients and frequently observed in subjects with mild cognitive impairment or dementia. Inter-observer agreement improved from κ = 0.71 to κ = 0.82 after protocol refinement. Among amyloid-positive patients with cognitive impairment, 11.2% exceeded proposed CMB thresholds for anti-amyloid therapy eligibility.

DISCUSSION: Standardized CMB assessment improves reliability in memory-clinic populations. Given its growing impact on treatment eligibility and safety, consistent evaluation is essential for patient management.},
}

@article {pmid42817135,
year = {2026},
author = {Chen, H and Xia, C and Li, Y and Sun, W and Wang, Y},
title = {ZhiXiaoSanZheng Decoction Ameliorates HGPA-induced HK-2 Cell Injury and Mitochondrial Metabolic Imbalance by Regulating the AMPK/PPARα/CPT1A Pathway.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128525206260914061658},
pmid = {42817135},
issn = {1873-4286},
abstract = {INTRODUCTION: ZhiXiaoSanZheng Decoction (ZXSZD) is a modern clinical Traditional Chinese Medicine (TCM) formula that exerts favorable clinical efficacy in the treatment of Diabetic Kidney Disease (DKD). However, its potential renal tubular protective mechanism remains unclear.

METHODS: Ultra-high-performance liquid chromatography-tandem mass spectrometry was employed to analyze and characterize the chemical ingredients of ZXSZD. An in vitro cell model was established by stimulating HK-2 cells with High Glucose-Palmitic Acid (HGPA) to mimic the metabolic microenvironment of DKD. Oil Red O staining was performed to assess intracellular lipid accumulation. Western blot and immunofluorescence assays were used to determine the protein expression levels of key molecules in the AMPK/ PPARα/CPT1A signaling pathway. Additionally, mitochondrial membrane potential, intracellular ATP content, activities of mitochondrial respiratory chain complexes (I and IV), oxidative stress levels, and concentrations of inflammatory cytokines were quantified.

RESULTS: A total of 141 chemical ingredients were preliminarily identified in ZXSZD. In HGPA-induced HK- 2 cells, ZXSZD significantly attenuated intracellular lipid accumulation, upregulated the protein expression of p-AMPK, PPARα, and CPT1A, ameliorated energy metabolism impairment and mitochondrial dysfunction, and suppressed oxidative stress as well as inflammatory responses.

DISCUSSION: The results indicate that ginkgolide effectively binds and stabilizes the ApoE4 N-terminal domain, supporting its potential role in modulating a key pathological factor in Alzheimer's disease. Its superior pharmacokinetic profile and interaction dynamics compared with those of curcumin and resveratrol suggest broader therapeutic relevance. These in silico insights provide a mechanistic basis for further investigation into ginkgolide's neuroprotective effects.

CONCLUSION: ZXSZD ameliorates energy metabolism impairment and mitochondrial dysfunction in HGPAinduced HK-2 cells by activating the AMPK/PPARα/CPT1A signaling pathway, while also inhibiting oxidative stress and inflammation.},
}

@article {pmid42817879,
year = {2026},
author = {Zheng, W and Ma, Y and Su, C and Qiu, Z and Yan, Z and Xu, G and Geng, D and Wang, A},
title = {Non-invasive neuromodulation in Alzheimer's disease: toward brain-heart coupling as a candidate framework for biomarker-guided adaptive intervention.},
journal = {Reviews in the neurosciences},
volume = {},
number = {},
pages = {},
pmid = {42817879},
issn = {2191-0200},
abstract = {Alzheimer's disease (AD) has entered an era of biologically informed, disease-modifying therapy, yet durable clinical benefit remains limited, highlighting the need for complementary interventions. Noninvasive neuromodulation has emerged as a promising strategy, but the field is still largely organized by device categories, stimulation targets, and short-term cognitive outcomes. This framing alone does not readily account for the marked heterogeneity, stage dependence, and limited durability reported across studies. This narrative review synthesizes clinical, preclinical, and mechanistic evidence across repetitive transcranial magnetic stimulation, transcranial electrical stimulation, sensory gamma entrainment, focused ultrasound, photobiomodulation, and transcutaneous vagus nerve stimulation. We propose that device classification is a useful starting point but an incomplete explanatory framework, because different modalities have been linked, with varying levels of evidence, to overlapping processes involving network reconfiguration, autonomic regulation, neurovascular function, inflammatory signaling, and clearance-related biology. Against this background, we examine the brain-heart axis and the central autonomic network (CAN) as a candidate intermediate level at which central neural and peripheral physiological responses to stimulation might be jointly characterized. Building on this view, we propose a biomarker hierarchy that extends from heart rate variability to directional and time-varying brain-heart coupling measures, which could be tested as candidate markers of physiological state, target engagement, and treatment responsiveness. At present, however, there is no prospective evidence that brain-heart coupling causally mediates the therapeutic effects of neuromodulation in AD. We, therefore, present brain-heart coupling as a testable candidate framework for studying state dependence, target engagement, and, ultimately, biomarker-guided adaptive neuromodulation.},
}

@article {pmid42818400,
year = {2026},
author = {Algamal, M and Yokomizo, S and Ndambakuwa, W and Abdallah, S and Sanchez-Mico, MV and Gillani, R and da Silva, P and Rajput, A and Palanivelu, L and Lee, Y and Walsh, KR and Kumar, S and Kilic, K and El Khoury, J and Izzy, S and Kozberg, MG and Bacskai, BJ},
title = {Brain-resident myeloid cells promote rapid leukocyte adhesion in leptomeningeal vessels after anti-Aβ immunotherapy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.07.749938},
pmid = {42818400},
issn = {2692-8205},
abstract = {Anti-amyloid-β (Aβ) immunotherapy improves cognitive outcomes in Alzheimer's disease (AD) but is associated with amyloid-related imaging abnormalities (ARIA), through poorly understood mechanisms. To define how anti-Aβ antibodies acutely engage brain immune and vascular compartments, we developed a longitudinal in vivo two-photon imaging platform to track microglial dynamics, peripheral immune cell recruitment, and vascular responses in APP/PS1 mice. Anti-Aβ antibodies, including aducanumab and lecanemab, rapidly initiated microglial activation and spatial reorganization within 24 hours of dosing, with recruitment to plaque-associated regions, stabilizing plaque growth. Aducanumab and lecanemab also triggered a rapid and transient cerebrovascular immune response characterized by rolling and adhesion of peripheral immune cells along leptomeningeal vessels, accompanied by endothelial activation. Immune cell characterization revealed recruitment of innate immune cells (Iba1[+]Ki67[+] monocytes and Ly6G[+] neutrophils) and proliferative CD3[+] T cells into the vascular compartment following treatment. Prophylactic treatment with high-dose dexamethasone reduced the number of adherent cells without affecting microglial activation. Depletion of brain-resident immune cells similarly reduced peripheral immune cell recruitment, supporting their contribution to leukocyte recruitment. Postmortem brain tissue from an AD patient treated with lecanemab showed higher proliferation-associated monocyte signature scores, suggesting translational relevance to the proliferative myeloid response observed in our mouse models. These findings demonstrate that anti-Aβ immunotherapy rapidly initiates a coordinated central and peripheral immune response at the leptomeningeal interface. These early immune-vascular interactions represent a plausible initiating mechanism for ARIA and provide a mechanistic framework to guide strategies for mitigating ARIA risk.},
}

@article {pmid42818410,
year = {2026},
author = {Stricker, NH and Boots, EA and Taylor, R and Fan, WZ and Frank, RD and Christianson, TJ and Stricker, JL and Kremers, WK and Machulda, MM and Aduen, PA and Lucas, JA and Hughes, MA and Karstens, AJ and Day, GS and Lachner, C and Graff-Radford, NR and Hassenstab, J and Mielke, MM and Jack, CR and Boeve, BF and Graff-Radford, J and Petersen, RC},
title = {Diagnostic accuracy of remote self-administered digital cognitive assessment by clinical diagnosis and Alzheimer's disease PET imaging biomarkers.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.20.26362296},
pmid = {42818410},
abstract = {INTRODUCTION: Cognitive characterization is increasingly important for Alzheimer's disease treatment decisions, highlighting the need for scalable cognitive assessment. We evaluated the diagnostic accuracy of a remote self-administered cognitive screening battery, Mayo Test Drive (MTD), across clinically and biologically defined groups.

METHODS: In this prospectively designed study, 2,131 cognitively unimpaired (CU) and 118 cognitively impaired participants, including 96 with mild cognitive impairment and 22 with mild dementia (MCI/DEM), were recruited from observational cohort studies and completed MTD remotely (mean age=70 years, SD=12; 48% male; mean education=16 years, SD=2). Clinical diagnoses were determined by multidisciplinary consensus independently of MTD. Amyloid- and tau-PET were available for 1,224 participants. Logistic regression estimated associations between MTD and CU versus MCI/DEM, CU A-versus MCI/DEM A+, and A-T-versus A+T+. MTD diagnostic accuracy was compared with person-administered cognitive measures. Sensitivity and specificity across score types and comparison groups were examined.

RESULTS: MTD showed excellent discrimination of CU versus MCI/DEM (AUC=.89; 95% CI=.87-.92), and discriminability remained high for CU versus MCI (AUC=.88; 95% CI=.85-.92). Discriminability was highest when comparing CU A- and MCI/DEM A+ groups (AUC=.95; 95% CI=.92-.97). MTD outperformed estimated MMSE (p=.02) and was comparable to Mayo-PACC (p=.71) for A-T-versus A+T+ discrimination (AUC=.76; 95% CI=.71-.81). Combining both raw score and normative score cutoffs helped balance sensitivity and specificity relative to use of either cutoff in isolation. A two-stage interpretation framework further improved sensitivity while maintaining clinically useful specificity and informed development of an interpretation guide.

DISCUSSION: A remote self-administered digital cognitive assessment showed strong diagnostic accuracy for detecting MCI and mild dementia in a large, primarily population-based cohort. The remote, self-administered MTD composite also showed comparable performance to established in-person cognitive composites for differentiating amyloid and tau-defined biomarker groups. Remote self-administered digital cognitive assessment may complement existing cognitive evaluation approaches and support scalable cognitive characterization.

HIGHLIGHTS: Remote self-administered cognitive assessment showed strong differentiation of cognitively unimpaired and cognitively impaired participants.Diagnostic accuracy improved when amyloid PET biomarker status was incorporated.Remote assessment demonstrated sensitivity to amyloid and tau PET-defined Alzheimer's disease.Performance was comparable to established in-person composites and better than an in-person mental status screening measure.Digital cognitive screening may support scalable treatment and clinical trial workflows.},
}

@article {pmid42818421,
year = {2026},
author = {Wang, J and Pederson, AM and Flanders, MD and Choi, M and Buto, P and Sims, KD and Chen, R and Couch, E and Gilsanz, P and Hayes, KN and Zullo, AR and Stokes, A and Glymour, MM and Ackley, SF},
title = {Education and Alzheimer Disease Genetic Risk in Associations of GLP-1 Receptor Agonists With Dementia Among Adults With Type 2 Diabetes.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.09.04.26362304},
pmid = {42818421},
abstract = {OBJECTIVE: To evaluate whether educational attainment and Alzheimer disease genetic risk were associated with GLP-1 receptor agonist initiation and dementia incidence and whether adjustment for these measured factors materially changed the estimated association between GLP-1 receptor agonist initiation and incident dementia among adults with type 2 diabetes.

RESEARCH DESIGN AND METHODS: We conducted an observational cohort study using linked electronic health record, survey, and genetic data from 14,364 All of Us Research Program participants with type 2 diabetes. We estimated associations of educational attainment and Alzheimer disease genetic risk with treatment initiation and incident dementia and compared GLP-1 receptor agonist initiators with initiators of non-sodium-glucose cotransporter 2 inhibitor second-line therapies, with a separate sodium-glucose cotransporter 2 inhibitor comparison. Models were estimated before and after additional adjustment for educational attainment, APOE ε4, and non-APOE genetic risk.

RESULTS: Among 14,364 participants (mean age, 60.2 years; 54.2% female), the mean follow-up duration was 4.3 years. The estimated hazard ratio for dementia comparing GLP-1 receptor agonist initiation with non-SGLT2 inhibitor second-line therapy was 0.85 (95% CI 0.64-1.12) before adjustment for education or Alzheimer disease genetic risk and 0.84 (95% CI 0.64-1.12) after adjustment for educational attainment, APOE ε4, and non-APOE genetic risk.

CONCLUSIONS: Among adults with type 2 diabetes, adjustment for measured educational attainment and Alzheimer disease genetic susceptibility produced little change in the estimated association between GLP-1 receptor agonist initiation and incident dementia. These findings do not exclude confounding by these factors in other populations or residual confounding from socioeconomic, clinical, behavioral, and health-care-related factors.

HIGHLIGHTS: Observational studies have reported associations between GLP-1 receptor agonist use and lower dementia risk, but important social and genetic factors are often unavailable in electronic health record data.We examined whether educational attainment and Alzheimer disease genetic susceptibility were associated with treatment initiation and dementia and whether adjustment for these factors changed GLP-1 receptor agonist-dementia estimates.Adding measured education and genetic susceptibility produced little change in the estimated conditional hazard ratios.These results do not exclude residual confounding and should not be interpreted as evidence that GLP-1 receptor agonists prevent dementia.},
}

@article {pmid42816032,
year = {2026},
author = {Fan, L and Jiang, H and Yi, M and Peng, W and Zhang, Z},
title = {Icariin enhances PINK1-associated mitophagy to attenuate NLRP3/GSDMD-related microglial pyroptosis and cognitive impairment in Alzheimer's disease.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {10},
pages = {1176-1190},
doi = {10.1016/S1875-5364(26)61213-7},
pmid = {42816032},
issn = {1875-5364},
mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Microglia/drug effects/metabolism ; PTEN-Induced Putative Kinase ; Mice ; *Mitophagy/drug effects ; *Flavonoids/pharmacology ; *Pyroptosis/drug effects ; *Protein Kinases/metabolism/genetics ; *Cognitive Dysfunction/drug therapy/metabolism/genetics ; Humans ; Mice, Transgenic ; Molecular Docking Simulation ; Male ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which microglia-mediated neuroinflammation contributes to disease progression. Icariin (ICA), a major bioactive flavonoid from Epimedium, has neuroprotective activity, but how it regulates mitochondrial quality control and inflammatory injury in microglia remains unclear. In the present study, APP/PS1 transgenic mice and Aβ1-42-stimulated BV-2 microglia were used to examine the effects of ICA on mitophagy, mitochondrial stress, NLRP3/GSDMD-related pyroptotic changes, and neuroinflammation. Behavioral testing, histological analysis, transcriptomic profiling, immunofluorescence, Western blotting, ELISA, molecular docking, molecular dynamics simulation, cellular thermal shift assay, Mdivi-1 co-treatment, and siRNA-mediated Pink1 knockdown were performed. ICA improved cognitive deficits in APP/PS1 mice and reduced microglial inflammatory activation. Transcriptomic and experimental analyses showed that ICA enhanced mitophagy-related responses, restored mitochondrial membrane potential, and reduced excessive mitochondrial reactive oxygen species accumulation. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay supported potential engagement of ICA with PINK1. ICA also reduced NLRP3 inflammasome-associated inflammatory injury, GSDMD-related pyroptotic changes, and IL-1β and IL-18 release. In APP/PS1 mice, Mdivi-1 co-treatment weakened the anti-inflammatory effects of ICA. In Aβ1-42-stimulated BV-2 microglia, Pink1 knockdown reduced ICA-induced LC3/TOM20 colocalization and partially reversed the inhibitory effects of ICA on NLRP3 inflammasome-associated inflammatory markers. Overall, ICA enhances PINK1-associated mitophagy, alleviates mitochondrial stress, and attenuates NLRP3/GSDMD-related microglial pyroptotic injury in AD-related models. These findings suggest that PINK1-associated mitochondrial quality control contributes to the neuroprotective effects of ICA.},
}

Animals
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics
*Microglia/drug effects/metabolism
PTEN-Induced Putative Kinase
Mice
*Mitophagy/drug effects
*Flavonoids/pharmacology
*Pyroptosis/drug effects
*Protein Kinases/metabolism/genetics
*Cognitive Dysfunction/drug therapy/metabolism/genetics
Humans
Mice, Transgenic
Molecular Docking Simulation
Male

@article {pmid42816035,
year = {2026},
author = {Zhu, M and Wang, Y and Tang, H and Sun, Y and Feng, X and Wang, Q and Kuang, H},
title = {Data mining and multi-omics profiling to reveal the mechanisms of cold/hot property of traditional Chinese medicine in Alzheimer's disease treatment.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {10},
pages = {1221-1236},
doi = {10.1016/S1875-5364(26)61216-2},
pmid = {42816035},
issn = {1875-5364},
mesh = {Animals ; Humans ; Rats ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Data Mining ; *Drugs, Chinese Herbal/pharmacology ; Gastrointestinal Microbiome/drug effects ; Medicine, Chinese Traditional ; Metabolomics ; Multiomics ; Oxidative Stress/drug effects ; Proteomics ; },
abstract = {Alzheimer's disease (AD) is a severely debilitating condition that significantly hampers independent living, with no effective treatments currently available. Traditional Chinese medicine (TCM) has shown substantial promise in both preventing and alleviating AD symptoms. The medicinal properties-specifically hot, warm, cool, and cold-serve as a critical link between TCM theory and clinical application. However, the majority of research has concentrated on individual herbs for AD, with relatively few comprehensive studies exploring the biological mechanisms through which these herbs exert their medicinal properties. In this context, data mining, network pharmacology, and multi-omics approaches, including metabolomics, gut microbiota analysis, and proteomics, were employed to elucidate the effects and mechanisms of action of three hot/warm property herbs (THPH) and three cold/cool property herbs (TCPH) in the treatment of AD. Findings indicated that the herbs effective against AD primarily possess warm properties. THPH demonstrated a significant enhancement in cognitive, learning, and memory functions in AD rat models when compared to TCPH, potentially achieving therapeutic effects by boosting the synthesis of the neurotransmitter acetylcholine. Furthermore, THPH modulated energy metabolism, corrected metabolic imbalances in both brain and serum within AD rat models, inhibited oxidative stress, restored synaptic plasticity-related proteins and signaling pathways, and maintained intestinal microbiota homeostasis. Consequently, this study offers valuable insights into the therapeutic implications of the hot (warm) and cold (cool) properties of TCM in the management of Alzheimer's disease.},
}

Animals
Humans
Rats
*Alzheimer Disease/drug therapy/metabolism/genetics
Data Mining
*Drugs, Chinese Herbal/pharmacology
Gastrointestinal Microbiome/drug effects
Medicine, Chinese Traditional
Metabolomics
Multiomics
Oxidative Stress/drug effects
Proteomics

@article {pmid42816815,
year = {2026},
author = {Mar, J and Arrospide, A and Handels, R and Soto-Gordoa, M},
title = {Economic model of Alzheimer's disease that incorporates the uncertainty associated with measuring efficacy in clinical trials.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490543},
doi = {10.1177/13872877261490543},
pmid = {42816815},
issn = {1875-8908},
abstract = {BackgroundClinical trials of Alzheimer's disease (AD) treatments are ongoing, and uncertainty about their efficacy is a key factor in their evaluation.ObjectiveThe objective of this study was to propose a new methodological approach for the economic evaluation of treatments to account for the uncertainty associated with measuring efficacy in clinical trials and the waning effect.MethodsA discrete event simulation model was built using data from a synthetic clinical trial dataset to model typical patient-level natural history trajectories of Clinical Dementia Rating scores from mild cognitive impairment to severe dementia using mixed regression models for repeated measures (MMRM). As the MMRM coefficients are correlated, this variability was incorporated into the model probabilistic sensitivity analysis using Cholesky decomposition. Uncertainty about treatment effect waning was addressed by scenario analysis (optimistic and pessimistic).ResultsAlthough the main contribution of this study is to describe an innovative model, the results of the hypothetical intervention are presented in the standard format of incremental cost-utility ratios (ICURs), cost-effectiveness and acceptability curves. Specifically, the ICUR of the hypothetical treatment ranged from €73,216 to €63,662 per quality-adjusted life year.ConclusionsWe present an innovative approach to the economic evaluation of Alzheimer's disease treatments, applying a Monte Carlo simulation approach (PSA) to two scenarios and shaping individual cognitive trajectories on a continuous scale to fit the target population of clinical trials. Its transparent design allows the economic model to be shared between the pharmaceutical company and the assessment agencies while keeping individuals' clinical trial data confidential.},
}

@article {pmid42816829,
year = {2026},
author = {Goncalo, AK},
title = {The role of neuroinflammation in the connections between autism spectrum disorder and Alzheimer's disease and related dementias: A review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491809},
doi = {10.1177/13872877261491809},
pmid = {42816829},
issn = {1875-8908},
abstract = {Recent evidence suggests a link between autism spectrum disorder (ASD) and early-onset Alzheimer's disease and related dementias (AD/ADRD), yet the mechanisms underlying this association remain poorly understood. This narrative review investigates whether early management of ASD may reduce the risk of developing AD/ADRD by targeting shared biological pathways. A literature search was conducted using PubMed and included English-language studies published from 1996 to 2026. Eligible studies addressed ASD, AD/ADRD, neuroinflammation, aging, or dementia, and included systematic reviews, meta-analyses, narrative reviews, clinical trials, randomized controlled trials, and translational animal studies. Studies lacking discussion of mechanisms relevant to ASD, neuroinflammation, aging, or dementia were excluded. Search terms included AD, dementia, ASD, inflammation, pregnenolone, omega-3, prednisolone, celecoxib, minocycline, N-acetylcysteine, sulforaphane, histamine receptor agonists, and GABA. Additional studies were identified through reference list screening. Of 170 records identified, 133 met the inclusion criteria and formed the basis for the review. Findings indicate that neuroinflammation is a central mechanism linking ASD-related comorbidities with established AD/ADRD risk factors. The evidence suggests that reducing neuroinflammation, particularly through interventions targeting microglial activation during childhood or early adulthood, may lower the likelihood of early-onset AD/ADRD in individuals with ASD. Although current evidence is primarily theoretical and indirect, it supports further investigation of anti-inflammatory strategies as potential preventive interventions. The review concludes by proposing future empirical studies to test whether early neuroinflammation-targeted treatment in ASD can reduce the incidence of early-onset AD/ADRD.},
}

@article {pmid42816931,
year = {2026},
author = {Xiao, H and Wang, J and Wan, S},
title = {WIMOAD: Weighted Integration of Multi-Omics data with meta learning for Alzheimer's Disease diagnosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261491975},
doi = {10.1177/13872877261491975},
pmid = {42816931},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD), the most prevalent subtype of dementia, is characterized by a gradual decline in brain cognitive function. Early detection is critical for initiating timely interventions that may delay the severe progression of the disease. Recent advances in next-generation sequencing (NGS) offer promising, non-invasive, and cost-effective strategies for AD screening. However, most current approaches rely on single-omics data, which fail to capture the complex biological heterogeneity among individuals.ObjectiveTo develop a user-friendly and efficient framework that incorporates blood-based multi-omics for stage-specific AD classification and detects genetic markers associated with disease pathology.MethodsWe introduce WIMOAD, a stacking ensemble and weighted multi-omics integration for AD diagnosis. It leverages paired gene expression and methylation data from ADNI and presents a meta learning framework for multi-cognitive stage classification during AD progression.ResultsAcross tasks, WIMOAD consistently outperforms single-omics models and representative integration baselines, and surpasses existing integration methods in AD diagnosis. Its interpretability also facilitates the detection of novel biomarkers across different omics layers. The code is freely available at https://github.com/wan-mlab/WIMOAD.ConclusionsThe study believes WIMOAD is an interpretable, cost-effective and promising integrative framework for accurate AD diagnosis and biomarker discovery across different cognitive stages utilizing blood-based data, which eventually will have consequential impacts on early treatment intervention and personalized therapy design for AD.},
}

@article {pmid42816978,
year = {2026},
author = {Anshika, and Tailor, NK},
title = {Cinnamic Acid-based Hybrid Molecules as Multitarget Therapeutic Agents for Cancer, Alzheimer's Disease, and Malaria: A Review.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575495727260909051459},
pmid = {42816978},
issn = {1875-5607},
abstract = {Molecular hybridization has emerged as a powerful medicinal chemistry approach for address the limitations of conventional single-target therapeutics, particularly in the treatment of complex, multifactorial diseases. This strategy involves integrating two or more pharmacologically active pharmacophores into a single molecular framework, enabling enhanced biological activity, multi-target interactions, and improved pharmacokinetic properties. Among the diverse scaffolds investigated for hybrid drug design, cinnamic acid has attracted considerable attention owing to its structural simplicity, synthetic accessibility, and broad spectrum of biological activities. The incorporation of cinnamic acid into hybrid molecules has generated a wide range of compounds with improved therapeutic potential and selectivity. The pharmacological effects of cinnamic acid hybrids are associated with the modulation of key enzymes, including α-glucosidase, α-amylase, and acetylcholinesterase, as well as important signaling pathways such as NF-κB, COX-2, iNOS, PI3K/Akt/mTOR, and MAPK/ERK. These molecular interactions contribute to their diverse biological activities and therapeutic applications. This review provides a comprehensive overview of recent developments in cinnamic acid-based molecular hybrids, emphasizing design strategies, structure- activity relationships, pharmacological properties, and underlying mechanisms of action. Particular attention is given to their anticancer, neuroprotective, and antimalarial therapeutic applications. Furthermore, the review critically examines the advantages and current challenges of cinnamic acid hybridization and highlights future research directions. Overall, cinnamic acid-based molecular hybrids represent a promising platform for the development of multifunctional therapeutic agents with enhanced efficacy and broader clinical potential.},
}

@article {pmid42816980,
year = {2026},
author = {Pal, T and Singh, P},
title = {Oleandrin and PBI-05204 for Neuroprotection in Alzheimer's Disease, Parkinson's Disease, and Stroke: Preclinical Mechanisms, Blood-brain Barrier Penetration, and Clinical Translation Perspectives.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575485020260907153210},
pmid = {42816980},
issn = {1875-5607},
abstract = {INTRODUCTION: Alzheimer's disease, Parkinson's disease, and ischemic stroke are increasingly becoming one of the major health concerns across the globe due to the scarcity of effective treatments for these conditions. Natural compounds like oleandrin and PBI-05204 that are extracted from Nerium oleander have been recognised for their promising qualities in the treatment and prevention of these conditions due to their ability to provide protection to the neurons in the brain.

METHODS: A systematic review was conducted to identify preclinical research articles related to oleandrin and PBI-05204 in the treatment of Alzheimer's disease, Parkinson's disease, and ischemic stroke. Searches were conducted on articles from January 2021 to March 2026 in Pub- Med/MEDLINE, Scopus, and Web of Science using the terms "oleandrin," "PBI-05204," "Nerium oleander," "blood-brain barrier," "neuroprotection," "Alzheimer," "Parkinson," and "stroke." Original in vitro or in vivo preclinical studies providing information on neuroprotective results, mechanistic information (BDNF, Nrf2-ARE, apoptosis, mitochondria), or information on blood-brain barrier permeability were included. Non-original articles (reviews, editorials), preclinical research not involving any neurobiological parameters, and articles in languages other than English were excluded.

RESULTS: Preclinical studies suggest that both oleandrin and PBI-05204 can diffuse across the BBB and provide neuroprotection. These molecules were shown to increase the expression levels of BDNF, promote ARE-dependent transcription, rehabilitate mitochondrial function, and regulate apoptosis. Though these results are highly hopeful, the major translational gap is in the ability to reproduce preclinical success in the clinical environment.

DISCUSSION: There is sufficient cellular-molecular evidence for the potential use of these compounds, namely oleandrin, as well as PBI-052040. Some challenges may arise when attempting to apply such observations as a new treatment modality at the clinical research stage. This is true for bioavailability, toxicity, and regulatory factors that need to be addressed.

CONCLUSION: Oleandrin and PBI-05204 make for very interesting compounds to consider for their neuroprotective properties in the context of neurodegeneration. Although there is promise in the preliminary human data from these compounds, there are also significant translational hurdles that must be cleared before their final application for human benefit.},
}

@article {pmid42809100,
year = {2026},
author = {Wu, Y and Li, S and Zhang, X and Xu, Q and Chen, B and Yang, W and Liu, M and Li, J and He, X and Li, J and Wu, W},
title = {A multi-omics and machine-learning framework reveals shared druggable targets for Alzheimer's disease and periodontitis and identifies amentoflavone and taraxerone as potential dual-action natural products.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42809100},
issn = {1432-1912},
abstract = {Alzheimer's disease (AD) and periodontitis (PD) are highly prevalent chronic disorders in ageing populations and share multiple pathological features, particularly persistent inflammatory and immune dysregulation. Despite increasing evidence supporting an association between the two diseases, the shared druggable molecular mechanisms underlying their comorbidity remain incompletely understood, and effective therapeutic strategies capable of simultaneously targeting shared disease-related processes are limited. This study aimed to identify shared druggable molecular candidates associated with AD and PD and to evaluate the potential biological effects of the natural products amentoflavone (AF) and taraxerone (TA) in AD-PD-related inflammatory cell models. An integrative strategy combining Mendelian randomisation (MR), transcriptomic profiling, machine learning, and structure-based virtual screening was used to identify and prioritise shared molecular candidates associated with AD and PD. Molecular docking and molecular dynamics (MD) simulations were performed to evaluate the predicted binding modes and interaction stability of AF and TA with selected core proteins. In vitro experiments were conducted using LPS-induced mouse BV2 microglia and mouse primary gingival fibroblasts (MGFs) to assess the effects of AF and TA, alone and in combination, on core-gene expression, inflammatory mediator secretion, oxidative stress, apoptosis, and iNOS/CD206-defined microglial activation states. MR, transcriptomic, and machine-learning analyses prioritised six shared key genes, including FCGRT, LTBP1, CD59, SPRED1, SURF2, and ZDHHC2, with FCGRT, SPRED1, and SURF2 selected for subsequent structural and cellular investigations. Molecular docking and MD simulations suggested stable predicted interactions of AF and TA with these three proteins. AF formed persistent hydrogen-bond networks, particularly in the SPRED1 and SURF2 complexes, whereas TA interactions were predominantly hydrophobic. MM-PBSA analysis yielded favourable binding free energies ranging from - 62.4 to - 99.7 kJ/mol. AF at 10 µM and TA at 20 µM were selected as non-cytotoxic working concentrations for subsequent cellular experiments. Both compounds partially restored LPS-associated alterations in FCGRT, SPRED1, and SURF2 expression, reduced TNF-α, IL-1β, and IL-6 secretion, increased IL-10 production, attenuated oxidative stress by reducing ROS, MDA, and NO levels while increasing SOD activity, decreased apoptosis, and shifted the iNOS/CD206-defined microglial activation profile away from an LPS-induced pro-inflammatory state toward an anti-inflammatory or repair-associated response. AF + TA co-treatment produced greater combined effects than either single treatment in several assays; however, quantitative combination analyses are required to determine whether these effects represent pharmacological synergy or additive interactions. This study identified FCGRT, SPRED1, and SURF2 as prioritised shared molecular candidates associated with AD and PD and provided computational and cellular evidence supporting further investigation of AF and TA as potential natural-product-based therapeutic candidates. AF and TA showed stable predicted interactions with the selected proteins and modulated gene-expression, inflammatory, oxidative-stress, apoptotic, and microglial-activation-related phenotypes in LPS-induced cellular models. These findings provide additional insight into the shared molecular landscape of AD and PD and support further experimental evaluation of AF and TA, including direct target-engagement studies, quantitative combination analyses, and in vivo validation.},
}

@article {pmid42809251,
year = {2026},
author = {Udenia, H and Midha, N and Verma, R and Bari, A and Dada, T},
title = {Cognitive impairment in glaucoma.},
journal = {Indian journal of ophthalmology},
volume = {74},
number = {10},
pages = {1451-1461},
doi = {10.4103/IJO.IJO_3157_25},
pmid = {42809251},
issn = {1998-3689},
mesh = {Humans ; *Glaucoma/complications/physiopathology ; *Cognitive Dysfunction/etiology/diagnosis/physiopathology ; *Intraocular Pressure/physiology ; },
abstract = {Glaucoma, while regarded as an isolated ocular disorder, is now increasingly recognized as a component of a wider neurological spectrum. An accumulating body of neuroimaging-based studies have revealed structural and functional changes in the brain that are analogous to those observed in Parkinson's and Alzheimer's disease. These changes are further associated with systemic disturbances, including autonomic dysfunction, neuroinflammation, and elevated cortisol levels. This mounting evidence may elucidate the increased susceptibility of cognitive impairment and dementia observed in individuals with glaucoma. This article presents a narrative review of the existing literature. A thorough search was conducted across various databases, including PubMed, Scopus, and the Embase Library, without restriction on year of publication. This review consolidates various lines of evidence that underscore the common characteristic between glaucomatous optic neuropathy and neurodegenerative disorders. A range of pharmacological (anti-dementia medication, nootropic agent, cerebral metabolizers, and neutraceuticals) and nonpharmacological strategies (regular physical activity, meditation, sleep optimization, and dietary modification) and emerging modalities-including noninvasive brain stimulation, nanotechnology-based drug delivery systems, and artificial intelligence-guided therapeutic models-are broadening the scope of management beyond traditional approaches that not only target intraocular pressure reduction but also may support overall neuro-cognitive wellbeing. The establishment of a multidisciplinary framework is also vital, wherein an ophthalmologist works in collaboration with neurologists, psychologists, and rehabilitation specialists to facilitate thorough cognitive evaluation and timely treatment. This review underscores the need of safeguarding both visual and cognitive functions by recognizing glaucoma as an ocular disorder and neurodegenerative condition, aiming to improve long-term outcomes and quality of life.},
}

Humans
*Glaucoma/complications/physiopathology
*Cognitive Dysfunction/etiology/diagnosis/physiopathology
*Intraocular Pressure/physiology

@article {pmid42810176,
year = {2026},
author = {Kumar, N and Kushwaha, VK and Singh, G and Ojha, S and Dash, AK and Shankar, G},
title = {Rivastigmine-centered molecular hybridization strategies for multi-targeted intervention in Alzheimer's disease: Advances (2020-2026).},
journal = {Bioorganic & medicinal chemistry},
volume = {143},
number = {},
pages = {118811},
doi = {10.1016/j.bmc.2026.118811},
pmid = {42810176},
issn = {1464-3391},
abstract = {Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disorder characterized by cholinergic dysfunction, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial impairment, metal dyshomeostasis, and chronic neuroinflammation, collectively leading to irreversible cognitive decline and neuronal degeneration. Despite decades of intensive research, currently approved therapeutic agents, including cholinesterase inhibitors (ChEI) and NMDA receptor antagonists, provide only symptomatic relief and do not substantially alter disease progression. Among the clinically available ChEI, rivastigmine (RIV) has attracted considerable attention owing to its dual inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), pseudo-irreversible mode of action, and established clinical efficacy in AD management. In recent years, RIV has emerged as a highly promising pharmacophoric scaffold for the development of multifunctional hybrid molecules designed according to the multi-target-directed ligand (MTDL) strategy to modulate multiple pathological pathways involved in AD simultaneously. This review comprehensively summarizes and critically analyzes advances reported from 2020 to 2026 in the design, synthesis, biological evaluation, and therapeutic potential of RIV-based hybrid molecules and scaffold modifications for AD treatment. The review places particular emphasis on the rational hybridization of RIV with diverse bioactive pharmacophores, including tryptamine, coumarin, flavonoids, melatonin, tacrine, ferulic acid, cannabidiol, benzimidazole, piperidine, aryloxacetic acid, and antioxidant motifs, to generate multifunctional agents with enhanced pharmacological profiles. The reviewed hybrids demonstrated remarkable multifunctional properties, including potent inhibition of AChE and BChE, suppression of Aβ aggregation, antioxidant and metal-chelating activities, anti-inflammatory effects, modulation of monoamine oxidases, neuroprotection, mitochondrial stabilization, and improved blood-brain barrier permeability. Several derivatives exhibited significantly greater potency and broader neuroprotective profiles than RIV itself, highlighting the therapeutic value of molecular hybridization approaches in AD drug discovery.},
}

@article {pmid42810623,
year = {2026},
author = {Palollathil, A and Najar, MA and Pervaje, R and Raju, R and Keshava Prasad, TS and Modi, PK},
title = {Bacopa monnieri Attenuates Alzheimer's Pathology by Modulating RNA Metabolism, Cellular Stress Responses, and Rho GTPase Signaling: Phosphoproteomic Insights from a Cellular Model of Alzheimer's Disease.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106268},
doi = {10.1016/j.neuint.2026.106268},
pmid = {42810623},
issn = {1872-9754},
abstract = {Alzheimer's disease is a multifactorial disease characterized by proteinopathy caused by senile plaques and neurofibrillary tangles, leading to neuroinflammation and neuronal damage. Bacopa monnieri, with its extensive usage in the Indian traditional medicinal system, Ayurveda, holds promise in enhancing memory and improving neuronal functions. We performed quantitative phosphoproteomics analysis to understand the temporal dynamics of protein phosphorylation involved in Bacopa monnieri-mediated neuroprotection in the Alzheimer's disease model of IMR-32 cells. The quantitative phosphoproteomics analysis identified 5488 phosphopeptides corresponding to 1427 phosphoproteins. Among the dysregulated peptides in the Aβ42 treatment group, 430 were significantly hyperphosphorylated, and 540 were significantly hypophosphorylated. In contrast, the Bacopa monnieri co-treatment group exhibited 64 significantly hyperphosphorylated peptides and 69 significantly hypophosphorylated peptides. The phosphoproteins altered by Aβ42 were involved in biological functions such as RNA splicing, neuron axonogenesis in the central nervous system, and positive regulation of tau-protein kinase activity. Bacopa monnieri restored key pathways altered by Aβ42, including RNA metabolism, cellular response to stress, signaling by Rho GTPases, and RHOBTB2 GTPase cycle. Kinase mapping of differentially expressed phosphoproteins using the KinMap tool identified CDK11B, CDK12, PRKAA1, PRPF4B, STK10, ROCK1 and ROCK2 as downstream effectors of Bacopa monnieri. The network analysis of restored proteins revealed tight interactions between proteins associated with splicing regulation and stress response. This study offers a comprehensive understanding of phosphoproteome alterations involved in Alzheimer's disease in response to neuroprotection by Bacopa monnieri, which may pave the way for developing therapeutic strategies.},
}

@article {pmid42810842,
year = {2026},
author = {Morato, X and Marquié, M and Tartari, JP and Lafuente, A and Sáez, ME and Montoliu-Gaya, L and Huber, H and Alegret, M and Jofresa, S and Buendía, M and Pancho, A and Aguilera, N and Ibarria, M and Diego, S and Cuevas, R and Cañada, L and Pérez-Cordón, A and Sanabria, A and De Rojas, I and Cano, A and Orellana, A and Montrreal, L and Rosende-Roca, M and Vargas, L and Espinosa, A and Ortega, G and Núñez-Llaves, R and Martínez-Lucas, M and Cantero-Fortiz, Y and Alarcón-Martín, E and Gurruchaga, M and Tárraga, L and Valero, S and Sanz-Cartagena, P and Mañes, S and Zetterberg, H and Ruiz, A and Boada, M},
title = {A single-center open-label, randomized, parallel-group controlled clinical trial on the long-term effect of the treatment with EGb 761 in blood markers of inflammation and neurodegeneration in patients with mild cognitive impairment: ACE-2020-EGb 761.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490130},
doi = {10.1177/13872877261490130},
pmid = {42810842},
issn = {1875-8908},
abstract = {BackgroundNeuroinflammation plays a central role in Alzheimer's disease (AD) pathology and other dementias. EGb 761, a standardized Ginkgo biloba extract, has shown potential anti-inflammatory and neuroprotective properties.ObjectiveThis study evaluated the effects of EGb 761 on plasma proteins related to inflammation and neurodegeneration, cognitive performance, and core AD biomarkers in individuals with mild cognitive impairment (MCI).MethodsWe conducted a 12-month randomized, controlled, open-label clinical trial with a 12-month extension phase in 100 patients with MCI recruited at a single center. During the first 12 months, participants were randomly assigned to EGb 761 or no treatment. In the extension phase, all participants received EGb 761 for an additional 12 months. Plasma samples were collected at baseline and at 6-month intervals throughout both phases. Inflammatory and neurological proteomic profiles were assessed using the Olink Inflammation and Neurology panels. AD biomarkers including Aβ40, Aβ42, Aβ42/40 ratio, GFAP, NfL, and pTau231 were measured in plasma. Clinical, neurological, and neuropsychological assessments were performed at each visit.ResultsEGb 761 was associated with nominally significant longitudinal decreases in 15 plasma proteins linked to innate immunity and axon guidance, replicated in the delayed-start group.ConclusionsEGb 761 exposure is associated with longitudinal modulation of serum markers associated with systemic inflammation and neurodegeneration in MCI. Larger placebo-controlled biomarker-driven trials are warranted to confirm whether this translates into clinically meaningful neuroprotection.Trial registration:Registro Español de estudios clínicos (REec) 2020-003776-41, ClinicalTrials.gov NCT05594355, https://clinicaltrials.gov/study/NCT05594355.},
}

@article {pmid42811665,
year = {2026},
author = {Padilla, VJ and Otte, J and Sanford, K and Scullin, M and Corlett, C and Elkins, G},
title = {Hypnosis intervention for sleep quality in caregivers of individuals with Alzheimer's Disease.},
journal = {The American journal of clinical hypnosis},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/00029157.2026.2713606},
pmid = {42811665},
issn = {2160-0562},
abstract = {Poor sleep quality is a common health issue among caregivers of adults with Alzheimer's Disease and Related Dementias (ADRD). Behavioral interventions such as hypnosis have been proposed for improving sleep in this population since pharmacological measures can impair their ability to wake up readily to provide care. The present pilot study aimed to determine the feasibility of a hypnosis intervention program for improving sleep quality in caregivers of individuals with ADRD. A sample of 21 eligible adults was randomly assigned to either a self-administered hypnosis or a sham hypnosis group. The findings indicated feasibility of accrual, randomization, and intervention delivery. The mean treatment satisfaction rating score was 8.75 (SD = 1.28) in the treatment group, on a 0-to-10 numerical rating scale (0 = highly dissatisfied, 10 = highly satisfied). The mean ease-of-use rating for the treatment procedures was 8.50 (SD = .93) in the treatment condition. Results found improvements in sleep quality and duration as measured by the Pittsburgh Sleep Quality Index and sleep diaries.},
}

@article {pmid42812254,
year = {2026},
author = {Zhou, X and Hu, Y and Yang, Z},
title = {A meta-analysis of the effects of combined interventions centered on cognitive training on cognition, executive function, and negative emotions in patients with Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1883995},
pmid = {42812254},
issn = {1664-2295},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Cognitive Training ; *Executive Function/physiology ; *Emotions/physiology ; *Cognition/physiology ; Cognitive Enhancement ; Combined Modality Therapy ; Exercise Therapy ; Randomized Controlled Trials as Topic ; },
abstract = {OBJECTIVE: To systematically compare the effects of five intervention strategies centered on Cognitive Training (CT), including Routine Care (RC), CT, Physical Exercise (PE), Cognitive Plus Exercise Training (CET), and Cognitive Plus Non-Invasive Brain Stimulation (CNIBS), on cognitive function, executive function, and negative emotions in patients with Alzheimer's disease, using a network meta-analysis. The relative efficacy of different interventions was ranked to provide evidence-based support for optimizing combined treatment strategies in clinical practice.

METHODS: PubMed, Embase, Web of Science, Cochrane Library, and EBSCO databases were systematically searched to identify randomized controlled trials on CT and its combined interventions for Alzheimer's disease published from database inception to April 2026. A network meta-analysis was conducted within a frequentist framework using Stata 17.0 software. The efficacy of interventions was ranked using the surface under the cumulative ranking curve.

RESULTS: A total of 19 randomized controlled trials involving more than 2,000 patients were included. The network meta-analysis showed that, for cognitive function, CNIBS (SUCRA = 75.4%) and CET (SUCRA = 72.4%) ranked first and second, respectively, and were significantly superior to RC and single interventions. For executive function, CET ranked highest (SUCRA = 99.9%) and was significantly superior to PE alone (SMD = 3.71, 95% CI: 3.16 to 4.26) and RC (SMD = 1.69, 95% CI: 0.48 to 2.91), other interventions do not offer a significant advantage over RC. For negative emotions, CET ranked highest (SUCRA = 83.7%), followed by PE alone (SUCRA = 57.9%), and CNIBS was also superior to CT alone (SMD = 1.07, 95% CI: 0.53 to 1.61).

CONCLUSION: Combined interventions centered on CT are superior to single interventions in improving multidimensional symptoms in patients with Alzheimer's disease. Among them, CET shows the most prominent advantages in improving executive function and negative emotions, whereas CNIBS shows the greatest effect on overall cognitive function. In clinical practice, individualized intervention strategies should be selected according to the primary rehabilitation goal.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Cognitive Training
*Executive Function/physiology
*Emotions/physiology
*Cognition/physiology
Cognitive Enhancement
Combined Modality Therapy
Exercise Therapy
Randomized Controlled Trials as Topic

@article {pmid42812304,
year = {2026},
author = {Ji, D and Zhao, J and Huang, X and Liu, X and Yang, Q and Li, X and Yan, L and Gao, D and Xiao, Y},
title = {A coordinated multi-target approach based on chondroitin sulphate nano-selenium mitigates Alzheimer's disease pathologies in APP/PS1 mice.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1936198},
pmid = {42812304},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a severe neurodegenerative disorder characterised by progressive memory loss and cognitive decline. Because of the lack of effective treatment modalities for AD, novel therapeutics that could delay the progression of AD are urgently required. In this study, the neuroprotective effects and mechanisms of chondroitin sulphate nano-selenium (CS@Se) were investigated by using APPSwe, PSEN1dE9 (APP/PS1) transgenic mice. We found CS@Se to exhibit potent multi-targeted anti-AD effects, and it showed excellent ability to effectively alleviate neuropathy and cognitive dysfunction. Behavioural experiments showed that CS@Se improved learning and memory capacity and enhanced motor activity. Mechanistically, CS@Se upregulated A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) expression while downregulating the levels of amyloid precursor protein (APP) and beta-secretase 1 (BACE1). Further studies revealed that CS@Se could reduce β-amyloid (Aβ) deposition and inhibit tau phosphorylation by promoting APP hydrolysis and inhibiting the glycogen synthase kinase (GSK)-3β signalling pathway in APP/PS1 mice. Additionally, CS@Se could alleviate oxidative stress damage, neuroinflammation, and cholinergic damage. In conclusion, CS@Se confers substantial neuroprotective effects by modulating several key pathological pathways, providing evidence for its multi-target therapeutic strategy against AD.},
}

@article {pmid42812519,
year = {2026},
author = {Cheung, EYW and Shea, YF and Chiu, PKC and Chan, KH and Zhang, H and Yam, KK and Bae, KT and Mak, HKF},
title = {Longitudinal patterns of regional cerebral blood flow during anti-amyloid therapy in mild cognitive impairment: a pilot ASL MRI case series.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1903239},
pmid = {42812519},
issn = {1663-4365},
abstract = {INTRODUCTION: The neurovascular effects of anti-amyloid therapy remain incompletely understood. Arterial spin labeling (ASL) MRI enables non-invasive quantification of regional cerebral blood flow (rCBF) and may provide insight into perfusion patterns observed over the treatment period.

METHODS: This pilot observational case series included participants with MCI or very early Alzheimer's disease undergoing anti-amyloid therapy (lecanemab), who underwent longitudinal pseudo-continuous ASL MRI at baseline and predefined follow-up timepoints. Regional rCBF was quantified across predefined cortical and subcortical regions of interest. A comparison group of amyloid-positive participants with MCI who did not receive anti-amyloid therapy underwent baseline ASL MRI. Vascular and metabolic risk factors, including white matter hyperintensity burden and biochemical parameters, were assessed to characterize potential confounding influences.

RESULTS: Within the treated group, increased rCBF was observed at early follow-up in several frontal, sensorimotor, and subcortical regions. No statistically significant longitudinal changes were detected at intermediate follow-up. At later follow-up, increased rCBF was observed in the cerebellar cortex, while decreased rCBF was observed in bilateral medial temporal regions. Vascular and metabolic risk profiles, including WMH burden, were broadly comparable between groups.

DISCUSSION: The observed rCBF trajectories demonstrate region-specific and time-dependent perfusion changes over the treatment period. Given the small sample size, absence of longitudinal imaging in the control group, and residual vascular confounding, these findings should be interpreted cautiously as exploratory and hypothesis-generating rather than evidence of treatment efficacy.},
}

@article {pmid42812614,
year = {2026},
author = {Kuang, Q and Li, S and Huang, W and Kuang, N and Liu, T and Huang, N and Luo, Y and Huang, J},
title = {TREM2-directed therapy in Alzheimer's disease: from therapeutic window to clinical translation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1938062},
pmid = {42812614},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, tau pathology, synaptic dysfunction, and a sustained neuroimmune response. Among immune-related targets, triggering receptor expressed on myeloid cells 2 (TREM2) is of particular interest because it is supported by human genetics, microglial biology, and expanding therapeutic development. TREM2 regulates microglial survival, phagocytosis, lipid handling, metabolic fitness, and plaque-associated responses, yet its therapeutic significance is more complex than a simple protective receptor model suggests. Although multiple TREM2-directed strategies have entered preclinical and early clinical development, recent evidence indicates that pharmacological target engagement does not necessarily translate into clinical benefit. We therefore propose that the therapeutic value of TREM2 is best understood through the concept of therapeutic window. TREM2 modulation is more likely to be beneficial when amyloid pathology is still being actively contained and microglial functional reserve remains preserved, whereas later disease stages, tau-associated neurodegeneration, receptor shedding, genetic heterogeneity, and pre-existing immune dysfunction may narrow or alter treatment benefit. Within this framework, soluble TREM2 (sTREM2) should be interpreted cautiously, as it may reflect receptor shedding, target engagement, microglial state, disease stage, or a combination of these processes rather than serving as a direct surrogate of efficacy. Viewed in this way, the central challenge of TREM2-directed therapy is to determine both when receptor modulation can still produce meaningful tissue protection and how the mode of receptor engagement shapes adaptive or maladaptive microglial programs.},
}

@article {pmid42813034,
year = {2026},
author = {Gao, Y and Li, ZK and Li, HN and Hu, JZ and Du, XZ and Yan, X and Liu, S},
title = {Cellular heterogeneity and multicellular mechanisms in the pathogenesis of late-life depression: insights from single-cell and spatial multi-omics.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1944035},
pmid = {42813034},
issn = {1664-3224},
mesh = {Humans ; Multiomics ; Animals ; Single-Cell Analysis ; *Depression/etiology/metabolism ; Aging ; Brain/metabolism/pathology ; },
abstract = {Late-life depression (LLD) is a heterogeneous disorder characterised by affective symptoms, cognitive decline, vascular burden, frailty, treatment resistance, and an increased risk of neurodegenerative progression, yet bulk molecular approaches may obscure the cell-type-specific alterations underlying this clinical and biological heterogeneity. This narrative review synthesises single-cell, single-nucleus, spatial, and multi-omic evidence concerning neuronal, glial, vascular, and peripheral immune alterations relevant to LLD, while distinguishing direct findings from clinically defined or older-adult depression cohorts from evidence extrapolated from major depressive disorder, ageing, mild cognitive impairment, Alzheimer's disease, and experimental models. The strongest current evidence implicates selective excitatory and inhibitory neuronal subtypes and astrocytes in prefrontal affective-cognitive circuit dysfunction, whereas endothelial and neurovascular-unit abnormalities, microglial reprogramming, oligodendrocyte-lineage dysfunction, hippocampal plasticity deficits, and peripheral immune remodelling represent biologically plausible but less well-validated mechanisms. Ageing-related cellular alterations, blood-brain barrier disruption, endothelial-astrocyte dysregulation, neuroinflammation, impaired myelin maintenance, and hippocampal vulnerability may interact to contribute to affective, cognitive, vascular, and treatment-resistant phenotypes. However, direct single-cell and spatial multi-omics evidence from clinically defined LLD cohorts remains scarce, and peripheral immune signatures should be interpreted primarily as accessible systemic correlates rather than direct measures of brain pathology. Overall, current evidence supports a hypothesis-generating multicellular framework rather than validated LLD-specific mechanisms or therapeutic targets. Future studies integrating single-nucleus and spatial multi-omics with longitudinal clinical phenotyping, neuroimaging, peripheral immune profiling, in situ validation, and functional perturbation are required to define LLD-specific cellular states, establish causal mechanisms, and identify clinically actionable biomarkers and therapeutic targets.},
}

Humans
Multiomics
Animals
Single-Cell Analysis
*Depression/etiology/metabolism
Aging
Brain/metabolism/pathology

@article {pmid42814589,
year = {2026},
author = {Singh, L and Gupta, GD and Singh, S},
title = {Neurobehavioral and Molecular Rescue by Dapagliflozin in Aluminum Chloride-Induced Alzheimer's Model: Possible Relevance of NF-κB and Aβ(1-42).},
journal = {Assay and drug development technologies},
volume = {},
number = {},
pages = {1540658X261486541},
doi = {10.1177/1540658X261486541},
pmid = {42814589},
issn = {1557-8127},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by the deposition of amyloid-β plaques in the hippocampus, leading to cognitive and behavioral impairments. This study investigated the neuroprotective outcome of Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor primarily used for glycemic control, which also exhibits notable anti-inflammatory, antioxidant, and neuroprotective properties. Using an aluminum chloride (AlCl3)-induced rat model of AD, the research evaluates behavioral, biochemical, and neuroinflammatory changes, particularly focusing on the nuclear factor kappa-B protein (NF-κB) signaling pathway. Rats were orally administered AlCl3 to induce AD-like pathology, followed by DAPA treatment (1 and 2 mg/kg, p.o.) over a 28-day period. Behavioral assessments, including the Morris water maze and Elevated Plus Maze, were used to evaluate spatial memory and anxiety. On day 29, hippocampal tissues were collected to assess neurotransmitter levels, oxidative stress markers (LPO, GSH, nitrite), and inflammatory cytokines (interleukin-1 beta, interleukin-6), along with the expression of NF-κB. AlCl3 exposure led to significant alterations in neurotransmitter balance (AChE, GABA, and glutamate), heightened oxidative stress, and increased neuroinflammatory responses. DAPA treatment significantly mitigated these changes, notably downregulating NF-κB, which correlated with decreased amyloid beta and expression in the hippocampus. These findings suggest that beyond its antidiabetic action, DAPA offers promising neuroprotection against AlCl3-induced neurotoxicity, potentially via modulation of the NF-κB signaling pathway.},
}

@article {pmid42815597,
year = {2026},
author = {Kahou Tadah, RB and Bilanda, DC and Ngapout Fifen, JR and Kengne, SF and Owona, PE and Akamba Ambamba, BD and Tcheutchoua, YC and Bidinga A Goufani, CR and Follesa, P and Kamtchouing, P and Dzeufiet Djomeni, PD},
title = {Neuroprotective effects of Isodon ramosissimus (Hook.f.) Codd (Lamiaceae) aqueous extract against scopolamine-induced Alzheimer-like phenotype.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122429},
doi = {10.1016/j.jep.2026.122429},
pmid = {42815597},
issn = {1872-7573},
abstract = {Isodon ramosissimus is traditionally used in folk medicine for the management of neurological disorders. However, its neuroprotective properties against scopolamine-induced cognitive impairments have not yet been scientifically investigated.

AIM OF THE STUDY: This study investigated the anti-amnesic and neuroprotective effects of the aqueous extract of Isodon ramosissimus (IrAE) in a scopolamine-induced Alzheimer's-like phenotype in rats.

MATERIALS AND METHODS: Liquid chromatography-mass spectrometry (LC-MS) and quantitative phytochemical analyses were performed to tentatively identify IrAE bioactive compounds. Forty-eight male Wistar rats were randomly assigned to six groups receiving saline, scopolamine (1 mg/kg), scopolamine plus donepezil (5 mg/kg), or scopolamine plus IrAE (75, 150, or 300 mg/kg) for 14 consecutive days. Learning and memory were evaluated using the novel object recognition and Morris water maze tests. Cholinesterase activity, oxidative stress biomarkers, and histopathological changes in the prefrontal cortex and hippocampus were also assessed.

RESULTS: Scopolamine induced significant cognitive deficits (p < 0.01), increased Acetylcholinesterase activity and oxidative stress (p < 0.01), and caused substantial neuronal damage. IrAE treatment significantly reversed learning and memory deficits (p < 0.01), attenuated acetylcholinesterase activity and oxidative stress (p < 0.01), and preserved cortical and hippocampal neurons from scopolamine's neurotoxic effects. LC-MS analysis tentatively identified oridonin, stigmasterol, chrysoeriol, ferruginol, and corosolic acid, compounds with reported cognitive-enhancing, antioxidant, anti-inflammatory, anticholinesterase, and neuroprotective activities.

CONCLUSION: IrAE exerts marked anti-amnesic and neuroprotective effects, associated with cholinergic and antioxidant modulation. These findings provide preliminary pharmacological support for the traditional use of IrAE, warranting further preclinical investigation of its potential in the management of cognitive disorders.},
}

@article {pmid42815878,
year = {2026},
author = {Zhang, XT and Murphy, M and Riordan, H and Wang, K and Esquivel, R and Xu, W and Zhang, X and Gong, X and Sun, Y and Lu, Y},
title = {Understanding Alzheimer's disease through biomarkers: pathology, progression, and clinical application.},
journal = {Bioanalysis},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/17576180.2026.2740372},
pmid = {42815878},
issn = {1757-6199},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide accounting for an estimated 60% to 80% of cases. Biomarkers play an integral role in AD randomized clinical trials (RCTs), providing objective measures of disease pathology, progression, and therapeutic efficacy. Key biomarkers, including amyloid-beta (Aβ), tau proteins, neuroinflammatory and neurodegeneration markers, as well as various neuroimaging modalities can help to facilitate the assessment of disease-modifying therapies, enable earlier detection of pathological changes before clinical symptoms emerge, and inform regulatory decision-making by demonstrating target engagement and possible treatment efficacy when linked to cognitive outcomes. This review examines the most salient biomarkers in AD RCTs and underlines their importance in advancing diagnostics, guiding therapeutic development, and improving clinical trial design to enable effective disease-modifying treatments. [Relevant literature was identified through searches of PubMed and Google Scholar for studies published through June 2026].},
}

@article {pmid42802831,
year = {2026},
author = {Miklitz, C and Shrestha, M and Philipp, W and Henk, N and Sprinkart, AM and Block, W and Luetkens, JA and Radbruch, A and Lehnen, NC and Nowak, S},
title = {Locally deployed large language model for real-world lecanemab eligibility pre-screening.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70495},
pmid = {42802831},
issn = {2352-8729},
abstract = {INTRODUCTION: The introduction of disease-modifying Alzheimer's therapies requires complex, labor-intensive patient screening. Cloud-based large language models (LLMs) could support this task but are often unsuitable for routine care due to data protection constraints.

METHODS: We evaluated an on-premises, open-weights LLM (gpt-oss-120b) for automated extraction of therapy-relevant variables for lecanemab eligibility from German memory clinic reports. In a two-stage design, LLM-based extraction prompts, a deterministic rule-based extractor, and a shared downstream rule-based classifier were optimized on a development set (n = 97) and evaluated on an independent hold-out set (n = 99), with expert consensus as ground truth.

RESULTS: The LLM-based pipeline achieved 94% accuracy and a Cohen's kappa of 0.90 on the hold-out set, significantly surpassing the rule-based comparator (80% accuracy) and demonstrating performance comparable to human experts.

DISCUSSION: A locally deployed, on-premises LLM may assist eligibility screening as a triage support tool, potentially facilitating access to novel therapies without compromising patient data privacy.},
}

@article {pmid42803225,
year = {2026},
author = {Jamhour, RMAQ and Salman, HA and Alshammari, M and Almuqati, AF and Fayed, MH and Al-Mazaideh, GM},
title = {Alzheimer's Disease: Silent Erosion of Memory - From Discovery to Modern Crisis and the Quest for a Cure.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050423446251215051844},
pmid = {42803225},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by a decline in cognitive abilities and memory impairment, representing the most common form of dementia worldwide. First described by Alois Alzheimer in 1906, AD continues to pose significant global health and socioeconomic challenges, with incidence anticipated to exceed 14 million cases by 2060. Despite decades of investigation, the specific pathophysiology -comprising multifactorial mechanisms such as genetic predisposition, environmental influences, lifestyle factors, amyloid-β (Aβ) plaques, neurofibrillary tangles, tau pathology, as well as vascular disease - remains incompletely understood. This review provides a comprehensive summary of the current knowledge regarding these mechanisms, and it explores the field's new therapeutic modalities, such as monoclonal antibodies, ultrasound-based treatments, and novel diagnostic tools based on biomarkers. It also discusses the socioeconomic burden of AD and regional challenges in the Middle East, as well as the impact of the COVID-19 pandemic on dementia care. While many of AD's underlying causes are aggressive and difficult to treat, new research in genetics, natural compounds, and groundbreaking therapies offers hope for better diagnosis and treatment. Above all, this study emphasizes the importance of having more effective chemotherapeutic or radiological approaches for ADs, as well as a robust medical system capable of providing these treatments to the patients.},
}

@article {pmid42803713,
year = {2026},
author = {Ippati, S and Torelli, F and Zamboni, G and Iavarone, A and Martorana, A and Botello, B and Cotton, S and Walker, C and Phillips, Z and Avitabile, A},
title = {Diagnosis and management of mild cognitive impairment and mild Alzheimer's disease dementia: Findings from an Italian real-world survey.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261490595},
doi = {10.1177/13872877261490595},
pmid = {42803713},
issn = {1875-8908},
abstract = {BackgroundThe identification and early diagnosis of mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia are critical for timely intervention, yet implementation of biomarker-based diagnostics in the Italian healthcare system remains limited.ObjectiveTo characterize the real-world diagnostic journey, barriers, and management pathways of MCI and mild AD dementia patients in Italy.MethodsData were drawn from the Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of Italian primary care physicians and specialists. Physicians reported on diagnostic assessments, biomarker testing, and treatment initiation for consulting patients with MCI/mild AD dementia.ResultsPhysicians provided data on 325 patients (mean age: 74.1 years; 48.3% female). Patients aged ≥75 had lower Mini-Mental State Examination scores at survey (p = 0.0028) and diagnosis (p = 0.0223) than patients aged <75 years. Short-term memory loss (87.6%) was the most common symptom. Delays in diagnosis were most commonly attributed to limited specialist access (55.8%), prolonged interval between consultations (27.0%), and restricted diagnostic resources (20.4%). Magnetic resonance imaging was the primary imaging modality (65.7%), while biomarker testing such as cerebrospinal fluid and amyloid positron emission tomography were performed in 15.9% and 16.3% of cases, likely hindered by patient's reluctance and cost, respectively, as indicated by specialist-perceived challenges in using biomarkers for early symptomatic AD diagnosis. Patients whose treatment was initiated by specialists were commonly prescribed acetylcholinesterase inhibitors (72.8%).ConclusionsDelays in MCI and mild AD dementia diagnosis persist alongside systemic barriers and limited biomarker use. Improving referral pathways and biomarker access is essential for timely diagnosis and management.},
}

@article {pmid42803723,
year = {2026},
author = {Yeo, D and Kim, S and Lee, K and Son, Y and Lee, H and Kim, S and Hwang, HS and Yon, DK},
title = {Spirometry-defined obstructive airflow limitation and risk of incident dementia: A nationwide cohort study in South Korea.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489594},
doi = {10.1177/13872877261489594},
pmid = {42803723},
issn = {1875-8908},
abstract = {BackgroundWhether spirometry-defined airflow limitation is independently associated with incident dementia and related disability burden remains unclear.ObjectiveTo investigate the association between obstructive airflow limitation and incident dementia and to estimate dementia-related years lived with disability (YLDs) in a nationwide cohort.MethodsWe conducted a nationwide population-based cohort study linking the Korea National Health and Nutrition Examination Survey (2014-2021) with national health insurance claims data. Adults aged ≥40 years with baseline spirometry and no prior dementia were included. Airflow limitation was defined as FEV1/FVC <0.70, with severity classified by percent-predicted FEV1. Inverse probability of treatment weighting balanced baseline covariates. Cox models estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for incident dementia. Dementia-related YLDs were calculated using Global Burden of Disease Study weights.ResultsDuring follow-up (2014-2023), 760 cases (4.79%) of dementia occurred among 15,854 adults. Normal pulmonary function was associated with lower dementia risk than airflow limitation (aHR, 0.62 [95% CI, 0.50-0.77]). Within the normal range, risk decreased across increasing FEV1/FVC tertiles (T1 [lowest], 0.76 [0.60-0.96]; T2, 0.63 [0.49-0.81]; T3 [highest], 0.45 [0.34-0.59]). Among those with airflow limitation, risk increased with severity (mild: 1.32 [0.95-1.84]; moderate: 1.87 [1.41-2.46]). Greater severity was also associated with higher YLDs.ConclusionsSpirometry-defined airflow limitation was associated with higher dementia risk and greater disability burden, suggesting impaired pulmonary function as a potential factor in dementia risk stratification and brain health.},
}

@article {pmid42803724,
year = {2026},
author = {Bruun, M and Rune Nielsen, T and Waldemar, G and Frederiksen, KS},
title = {Older adults' attitudes toward knowing their risk of Alzheimer's disease and preclinical diagnostic communication: A nationwide study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261489585},
doi = {10.1177/13872877261489585},
pmid = {42803724},
issn = {1875-8908},
abstract = {BackgroundCommunication about biomarkers and disclosure of Alzheimer's disease pathology is challenging. Earlier diagnosis has intensified this challenge, but evidence regarding communication of positive biomarker results for Alzheimer's disease to individuals with subjective cognitive decline remains limited.ObjectiveThe study aimed to investigate older adults' attitude toward knowing their risk of Alzheimer's disease, preferences regarding pre-biomarker counseling and diagnostic disclosure, and their views on the use of artificial intelligence in the diagnostic process when presented with a hypothetical scenario of subjective cognitive decline.MethodsWe conducted a cross-sectional nationwide questionnaire survey among an age-selected, sex- and residence-balanced sample from the Danish Civil Registration System where individuals with dementia, nursing home residency, or dementia medication use were excluded. An online questionnaire was sent to 30,000 participants.ResultsA total of 12,939 participants (aged 55-84 years, 53.3% female) answered at least one questionnaire item (response rate: 43.1%). More than two-thirds of the participants were interested in knowing their Alzheimer's disease risk status (76.4%). Information on treatment options, test reliability and risk prediction, along with written material, personal interaction and follow-up consultation, were rated as the most important topics. Simple graphical figures were preferred to accompany risk communication. Finally, 56.4% were positive toward use of artificial intelligence in diagnostics by physicians.ConclusionsOlder adults are interested in knowing their risk of developing Alzheimer's disease and trust physicians' use of artificial intelligence in the diagnostic process. Moreover, their preferences regarding information and methodology may help improve the current guidelines.},
}

@article {pmid42803728,
year = {2026},
author = {Ali, M and Shabbir, H and Shaharyar, M and Mukesh, S and Rodriguez, A and Afshani, M and Kalra, D and Koriesh, A},
title = {Efficacy and safety of aducanumab, lecanemab, and donanemab in Alzheimer's disease: A meta-analysis of randomized controlled trials.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261488812},
doi = {10.1177/13872877261488812},
pmid = {42803728},
issn = {1875-8908},
abstract = {BackgroundAnti-amyloid monoclonal antibodies offer a treatment strategy for early Alzheimer's disease, but their modest efficacy must be weighed against important safety concerns.ObjectiveTo evaluate the efficacy and safety of aducanumab, lecanemab, and donanemab in randomized placebo-controlled trials.MethodsPubMed, Cochrane, and ClinicalTrials.gov were searched through February 2026 for randomized placebo-controlled trials evaluating aducanumab, lecanemab, or donanemab in early symptomatic Alzheimer's disease. Outcomes included Clinical Dementia Rating-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Mini-Mental State Examination (MMSE), amyloid-related imaging abnormalities-edema/effusion (ARIA-E), amyloid-related imaging abnormalities-hemosiderin deposition (ARIA-H), and APOE ε4-stratified ARIA-E. Random-effects meta-analyses were performed.ResultsSeven trials were included. Treatment favored intervention for ADAS-Cog (SMD -0.15, 95% CI -0.21 to -0.10), CDR-SB (MD -0.41, 95% CI -0.63 to -0.18), and MMSE (MD 0.44, 95% CI 0.03 to 0.86), although effects were small. Treatment increased ARIA-E (23.9% versus 1.9%; RR 11.65, 95% CI 9.06 to 14.99) and ARIA-H (16.8% versus 6.8%; RR 2.45, 95% CI 1.94 to 3.09). Among treated participants with APOE ε4-stratified ARIA-E data, APOE ε4 carriers had higher ARIA-E risk than non-carriers (29.3% versus 13.8%; RR 2.10, 95% CI 1.67 to 2.64). Brain-volume loss, ventricular enlargement, and treatment-related deaths were narratively identified but not pooled.ConclusionsAducanumab, lecanemab, and donanemab showed statistically significant but small slowing of decline that may not reach patient-perceptible clinical meaningfulness. Increased ARIA risk and additional safety signals support cautious selection, imaging surveillance, and individualized risk-benefit discussions.},
}

@article {pmid42803964,
year = {2026},
author = {Joshi, N and Vaidya, B and Saha, P and Kashyap, M and Sharma, SS},
title = {Clemizole, a TRPC5 channel blocker rescues amyloid-β toxicity and cognitive impairment by modulating mitochondrial dysfunction and memory-related proteins.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42803964},
issn = {1432-1912},
abstract = {Amyloid β (Aβ)-induced neuronal dysfunction is a key pathological feature of Alzheimer's disease (AD), characterized by oxidative stress, mitochondrial impairment, and calcium dyshomeostasis. Transient receptor potential canonical 5 (TRPC5), a calcium-permeable cation channel, has been implicated in neurodegeneration, but its role in AD remains unclear. This study investigated TRPC5 involvement in Aβ-induced neurotoxicity and evaluated the neuroprotective potential of Clemizole, a TRPC5 blocker, in preclinical AD models. In SH-SY5Y cells, Aβ-induced neurotoxicity was assessed by measuring cell viability, intracellular and mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, and calcium influx. In rats, an intracerebroventricular (ICV) Aβ25-35 (10 μg) induced cognitive impairment model was used. Behavioral tests assessed cognitive function. Hippocampal TRPC5 expression and memory as well as calcium associated protein expressions (p-CaMKII, PSD-95, BDNF, calcineurin A) were analyzed, and acetylcholinesterase (AChE) activity was measured following 3 weeks of Clemizole (10 and 30 mg/kg) treatment. Aβ exposure reduced neuronal survival, increased ROS, disrupted mitochondrial membrane potential, and elevated calcium influx in vitro. Clemizole mitigated oxidative stress, restored mitochondrial function, and restored calcium homeostasis. In vivo, Aβ induced cognitive deficits and upregulated hippocampal TRPC5 expression in rats. Clemizole reduced TRPC5 levels, improved cognitive performance, enhanced p-CaMKII, PSD-95, and BDNF expression, decreased calcineurin A, and reduced AChE activity. TRPC5 contributes to Aβ-induced neurotoxicity and cognitive impairment, and Clemizole-mediated TRPC5 inhibition confers neuroprotection by restoring calcium balance and attenuating the decrease in memory-associated protein expression. These findings support TRPC5 as a potential therapeutic target in AD; however, further studies using a transgenic AD model are warranted before clinical translation.},
}

@article {pmid42807347,
year = {2026},
author = {Albarrán Morillo, C and Zheng, L and Ghanbarian, E and Khorsand, B and Glover, CM and Grill, JD and Sajjadi, SA and Ezzati, A},
title = {APOE and amyloid-tau pathology in cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70496},
pmid = {42807347},
issn = {2352-8729},
abstract = {INTRODUCTION: Apolipoprotein E (APOE) genotype shows well-established dose-dependent associations with higher amyloid in cognitively unimpaired (CU) adults. In contrast, associations with tau burden and cognition are less well characterized.

METHODS: We performed a cross-sectional analysis of CU participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4), Alzheimer's Disease Neuroimaging Initiative (ADNI), Wisconsin Registry for Alzheimer's Prevention (WRAP), and National Alzheimer's Coordinating Center (NACC) within the harmonized multi-cohort Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC) data. A total of 4380 CU participants were included with APOE genotype, amyloid PET, and cognitive data (memory, language, executive, and visuospatial function), including a subset of 758 with tau PET imaging.

RESULTS: Compared with ε33, ε24 (β = 18.340), ε34 (β = 23.850), and ε44 (β = 44.820) showed higher amyloid burden (all p < .001). Similarly, ε24 (OR = 4.180), ε34 (OR = 4.540), and ε44 (OR = 14.150) had higher odds of amyloid positivity (all p < .001). After adjustment for amyloid burden, ε4 carriers had higher tau burden in the entorhinal cortex (β = 0.026; false discovery rate [FDR] -adjusted p = 0.041) and amygdala (β = 0.040; FDR-adjusted p = 0.003). Higher tau burden was associated with lower memory (β = -0.439; FDR-adjusted p = 0.012) and language performance (β = -0.610; FDR-adjusted p = 0.020).

DISCUSSION: APOE ε4 showed a strong dose-dependent association with amyloid, with the highest levels observed among ε4 homozygotes. Associations between APOE and global tau were more modest and appeared to be driven mainly by ε4 homozygotes, while regional analyses showed localized APOE ε4-related associations in medial temporal regions. Independently, higher tau was associated with lower memory and language performance.},
}

@article {pmid42807723,
year = {2026},
author = {Quan, Q and Pan, R and Liu, H and Zheng, L and Zhang, R},
title = {Potential Role of Red Yeast Rice in the Prevention and Treatment of Alzheimer's Disease.},
journal = {International journal of medical sciences},
volume = {23},
number = {10},
pages = {3101-3111},
pmid = {42807723},
issn = {1449-1907},
mesh = {*Alzheimer Disease/prevention & control/drug therapy/diet therapy ; Humans ; *Biological Products/therapeutic use/pharmacology/chemistry ; Monascus/metabolism/chemistry ; Antioxidants/therapeutic use/pharmacology ; Neuroprotective Agents/therapeutic use/pharmacology ; Lovastatin/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; gamma-Aminobutyric Acid/therapeutic use/pharmacology ; Fermentation ; },
abstract = {Red Yeast Rice (RYR) fermented from Monascus is a traditional fermented product with both dietary and medicinal uses and is widely used for lipid regulation. Clinically, it is utilized to lower blood lipid levels and manage hyperlipidemia. Contemporary research indicates that RYR is abundant in secondary metabolites, such as monacolin K, Monascus pigments, and γ-aminobutyric acid, which contribute to its lipid-lowering, blood sugar-reducing, anti-inflammatory, neuroprotective, and antihypertensive properties. These metabolites may play a significant role in the prevention and treatment of Alzheimer's disease (AD) through mechanisms that include cholesterol-dependent pathways, anti-neuroinflammation, antioxidant activity, neuroprotection, modulation of intestinal flora, inhibition of high-risk factors for AD, and suppression of AD-related β-amyloid peptide deposition and tau protein hyperphosphorylation. Consequently, RYR demonstrates potential for a multi-component synergistic approach to preventing and treating AD. However, current research on the use of RYR for AD prevention and treatment remains limited. This review focuses on the primary functional substances in RYR, elucidates the anti-AD effects and mechanisms of each metabolite, analyzes the advantages of its multi-component and multi-target properties, and provides a foundation for the further development of RYR.},
}

*Alzheimer Disease/prevention & control/drug therapy/diet therapy
Humans
*Biological Products/therapeutic use/pharmacology/chemistry
Monascus/metabolism/chemistry
Antioxidants/therapeutic use/pharmacology
Neuroprotective Agents/therapeutic use/pharmacology
Lovastatin/therapeutic use/pharmacology
Amyloid beta-Peptides/metabolism
gamma-Aminobutyric Acid/therapeutic use/pharmacology
Fermentation

@article {pmid42808238,
year = {2026},
author = {Kuzuya, A and Ohara, T and Akamatsu, N},
title = {Plain language summary of the mechanisms behind epilepsy in Alzheimer's disease and the use of perampanel.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/14737175.2026.2733194},
pmid = {42808238},
issn = {1744-8360},
}

@article {pmid42808496,
year = {2026},
author = {Park, BY and Jo, SW and Park, TY and Kim, H and Kim, MS and Kang, SY and Cho, SJ and Kim, J and Kim, S},
title = {Feasibility and safety of repeated low-intensity ultrasound in amyloid PET-positive early Alzheimer's disease: A prospective pilot study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261493067},
doi = {10.1177/13872877261493067},
pmid = {42808496},
issn = {1875-8908},
abstract = {BackgroundLow-intensity ultrasound (LIUS) is a potential noninvasive neuromodulatory approach for Alzheimer's disease (AD), but clinical evidence on repeated stimulation in biomarker-confirmed early AD remains limited.ObjectiveTo evaluate the feasibility, safety, and exploratory clinical effects of a 4-week repeated LIUS protocol in amyloid positron emission tomography (PET)-positive early AD.MethodsTwenty patients with amyloid PET-positive prodromal AD or mild AD dementia underwent LIUS targeting bilateral frontal and temporal regions three times weekly for 4 weeks. Safety was assessed by neurological examinations and brain magnetic resonance imaging (MRI). Exploratory outcomes included the Trail Making Test-Black & White (TMT-B&W) parts A and B, Attention Questionnaire Scale (AQS), Korean version of Quality of Life (KQoL), Mini-Mental State Examination (MMSE), and Neuropsychiatric Inventory (NPI). Resting-state functional MRI was analyzed in an exploratory subset.ResultsNo severe adverse events occurred, and post-treatment MRI showed no intracerebral hemorrhage, microbleeding, or brain edema. Completion times decreased on TMT-B&W part A (105.3 ± 63.3 versus 84.2 ± 46.6 s, p = 0.012) and part B (280.1 ± 139.9 versus 212.8 ± 59.7 s, p = 0.038). NPI scores also decreased (9.8 ± 14.7 versus 4.5 ± 8.8, p = 0.006). KQoL, AQS, and MMSE did not change significantly.ConclusionsRepeated LIUS over 4 weeks was feasible and well tolerated in amyloid PET-positive early AD. Exploratory changes in executive function and neuropsychiatric symptoms were observed; however, the single-arm design precludes causal inference. Randomized, sham-controlled studies are warranted to determine the therapeutic potential of LIUS.},
}

@article {pmid42797438,
year = {2026},
author = {Gecili, İ and Ertuğrul, MS and Okkay, IF and Şenol, O and Okkay, U and Özkaraca, M and Al-Yaqoobi, Z and Bayram, C and Abd El-Aty, AM and Taghizadehghalehjoughi, A and Hacımüftüoğlu, A},
title = {Early Neuroprotective Effects of Erucic Acid and Gentisic Acid on Hippocampal Glutamate Concentrations and Alzheimer-like Molecular Alterations in an Intracerebroventricular Streptozotocin Rat Model.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
pmid = {42797438},
issn = {1424-8247},
support = {TDK-2021-9100//Atatürk University/ ; },
abstract = {Background: Alterations in glutamatergic homeostasis have been implicated in Alzheimer's disease, but the relationship between total hippocampal tissue glutamate and Alzheimer-like molecular alterations remains unclear. This study evaluated the early neuroprotective potential of gentisic acid (GA) and erucic acid (EA) in an intracerebroventricular streptozotocin (icv-STZ)-induced rat model of sporadic Alzheimer-like pathology. Methods: Sixty-four female Sprague-Dawley rats were randomly assigned to eight groups: control, sham, STZ, STZ + GA (100 or 200 mg/kg/day), STZ + EA (25 or 50 mg/kg/day), and STZ + memantine (10 mg/kg/day). Treatments began immediately after STZ and continued orally for 21 days. Behavioral performance was assessed by Morris water maze and passive avoidance tests. Total hippocampal tissue glutamate was quantified by LC-MS/MS. Neuronal degeneration was assessed histopathologically, whereas tau, amyloid-β, and AChE immunoreactivity and tau-, APP-, and AChE-related in situ hybridization signals were evaluated. Results: Compared with controls, STZ-treated rats exhibited poorer behavioral performance, higher total hippocampal tissue glutamate, greater neuronal degeneration, and increased molecular signals. GA and EA administration was associated with attenuation of these alterations, with generally stronger effects at higher doses. EA at 50 mg/kg/day showed the lowest mean total hippocampal tissue glutamate among treatment groups. GA at 200 mg/kg/day and EA at 50 mg/kg/day showed the most consistent preservation across behavioral, histopathological, and molecular endpoints. Conclusions: Early GA and EA administration was associated with neuroprotective effects in the icv-STZ model. Because treatment began immediately after STZ administration, the findings support early or preventive neuroprotection rather than reversal of established Alzheimer-like pathology. Total tissue glutamate measurements neither distinguish extracellular glutamate nor directly demonstrate glutamate-mediated excitotoxicity.},
}

@article {pmid42797479,
year = {2026},
author = {Bustelli, IB and Graça, SC and Santos, ÉVD and Lanaro, R and Linardi, A and Caetano, AL},
title = {Effects of Chronic Banisteriopsis caapi Extract Administration on Fibrillar Amyloid Deposition and Microglial Morphology in Aged PDGFB-APPSwInd Mice.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
pmid = {42797479},
issn = {1424-8247},
support = {2021/02469-2//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2021/06490-6//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 004/2022//Faculdade de Ciências Médicas da Santa Casa de São Paulo/ ; },
abstract = {Background/Objectives:Banisteriopsis caapi contains β-carboline alkaloids with neuropharmacological and immunomodulatory properties, but their effects during prolonged exposure in established amyloid pathology remain poorly characterized. This study investigated whether chronic intermittent B. caapi administration modifies behavioral performance, fibrillar amyloid pathology, and hippocampal microglial alterations in aged PDGFB-APPSwInd mice. Methods: Male wild-type (WT) and PDGFB-APPSwInd transgenic (TG) mice aged 15-18 months received B. caapi extract (1.5 mL/kg, oral gavage) or vehicle twice weekly for four weeks. Locomotor activity, anxiety-like behavior, and spatial recognition memory were assessed using the open-field, elevated-plus-maze, and object-location tests, respectively. Hippocampal fibrillar amyloid plaques were evaluated by Thioflavin-S staining, and microglial immunoreactivity and morphology were assessed using Iba1 immunofluorescence and morphometric analysis. Results: Chronic B. caapi administration did not consistently modify locomotor activity, anxiety-like behavior, or spatial recognition memory. In TG mice, treatment increased the number of hippocampal Thioflavin-S-positive fibrillar amyloid plaques, without corresponding changes in total Thioflavin-S-positive area or median plaque size. Microglial alterations were predominantly genotype-associated, with TG mice exhibiting changes in Iba1-labeled cell quantification and morphology, particularly in the CA1 region. B. caapi treatment did not significantly modify these genotype-associated morphological alterations. Conclusions: Chronic intermittent B. caapi exposure was associated with a selective change in fibrillar amyloid plaque number without parallel changes in plaque area, plaque size, behavioral performance, or microglial morphology. These findings expand current evidence regarding the biological effects of repeated B. caapi exposure in the context of established amyloid pathology.},
}

@article {pmid42798750,
year = {2026},
author = {Shimohama, S and Bun, S and Shikimoto, R and Tomioka, H and Takayama, T and Mimura, Y and Sasaguri, H and Sekiguchi, K and Nishimoto, Y and Iwabuchi, Y and Tabuchi, H and Nakahara, J and Mimura, M and Ito, D},
title = {Real-world implementation of lecanemab in Alzheimer's disease: A Japanese cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70492},
pmid = {42798750},
issn = {2352-8729},
abstract = {INTRODUCTION: Real-world evidence for lecanemab remains limited, particularly among Asian populations. We evaluated the feasibility, safety, biomarker profiles, and short-term clinical outcomes of lecanemab in practice in Japan.

METHODS: We screened 321 patients with early Alzheimer's disease (AD) and confirmed amyloid pathology using amyloid positron emission tomography (PET) or cerebrospinal fluid analysis. Plasma amyloid-β42/40 was assessed when available. Among these, 102 initiated lecanemab and underwent structured magnetic resonance imaging (MRI) surveillance with 6 months of follow-up.

RESULTS: Most treated patients had a Clinical Dementia Rating-Global (CDR-Global) score of 0.5 (96.1%), and 6-month treatment persistence exceeded 85%. Amyloid-related imaging abnormalities (ARIA), predominantly mild and asymptomatic ARIA-H, occurred in 11.4%, whereas no cases of isolated ARIA with effusion or edema (ARIA-E) were observed. One macrohemorrhagic and two moderate-severe radiographic ARIA with hemorrhage or hemosiderin deposition (ARIA-H) developed, which led to discontinuation of the treatment. Cognitive and functional measures remained generally stable over 6 months, with changes comparable to those reported in the phase 3 CLARITY-AD trial. Plasma-PET discordance highlighted the complementary value of multimodal biomarker interpretation.

DISCUSSION: Lecanemab was feasible and generally well tolerated under structured MRI monitoring in routine Japanese practice.},
}

@article {pmid42799832,
year = {2026},
author = {Hasan, A and Asfour, AAR and Qaba, H and Al-Sharabi, AA and Asfoor, A and Mohammed, S and Al-Adhreai, A and Güner, S and ALSaeedy, M},
title = {Mast Cells in Neuroimmune Interactions: Mechanisms, Pathophysiological Roles, and Therapeutic Implications.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42799832},
issn = {1559-1182},
mesh = {*Mast Cells/immunology/pathology/metabolism ; Humans ; Animals ; *Neuroimmunomodulation/physiology ; },
abstract = {Mast cells (MCs) are versatile immune cells that play a key role in neuroimmune interactions due to their strategic localization in barrier tissues and perineuronal sites, including the meninges, choroid plexus, thalamus, hypothalamus, and hippocampus within the central nervous system (CNS), as well as peripheral sites such as the skin, gastrointestinal tract, and dorsal root ganglia. They rapidly release stored and newly synthesized mediators, including histamine, tryptase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), substance P, and prostaglandins, which regulate nerve signaling, vascular function, and inflammation. This review presents a framework integrating MC differentiation with distinct CNS microenvironments to explain their neuroprotective and toxic roles. The anatomical and molecular basis of MC-neuron interaction is discussed, with emphasis on bidirectional signaling via neuropeptides, neurotransmitters, and cytokines. MC functions in the CNS are highlighted, including neuroprotection through synaptic plasticity and BBB integrity under homeostatic conditions, as well as neurotoxicity, where aberrant activation promotes BBB breakdown, microglial priming, and neuroinflammatory cascades. Furthermore, the roles in which mast cell dysfunction is implicated in neurodegenerative and psychiatric disorders are examined, including Alzheimer's disease (AD), where amyloid-β triggers MC degranulation, Parkinson's disease (PD), where α-synuclein induces MC activation, multiple sclerosis (MS), autism, anxiety, and depression, as well as peripheral neuroimmune conditions affecting the skin, gut-brain axis, and pain. Current and emerging mast cell-targeted therapies, including stabilizers, histamine receptor blockers, tryptase inhibitors, and anti-IgE biologics, are discussed, along with future challenges in mast cell-based neuroimmunological treatment.},
}

*Mast Cells/immunology/pathology/metabolism
Humans
Animals
*Neuroimmunomodulation/physiology

@article {pmid42800042,
year = {2026},
author = {Ho, BL and Yang, YH},
title = {Blood-based biomarkers in the anti-amyloid era of Alzheimer's disease: clinical utility, implementation challenges, and future directions.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/17582024.2026.2734618},
pmid = {42800042},
issn = {1758-2032},
abstract = {BACKGROUND: Implementation of disease-modifying anti-amyloid therapies for Alzheimer's disease remains constrained by the cost and procedural burden of positron emission tomography and cerebrospinal fluid testing. This review evaluates blood-based biomarkers in therapeutic pathways.

METHODS: PubMed/MEDLINE and Embase were searched for literature published from January 2018 onward, with earlier landmark studies included when relevant. Evidence was synthesized on plasma biomarkers in treatment eligibility, biological staging, longitudinal monitoring, therapeutic response, and risk stratification for amyloid-related imaging abnormalities.

RESULTS: Among assays, plasma p-tau217 consistently demonstrates the highest diagnostic accuracy for detecting cortical amyloid pathology across clinical settings. The plasma p-tau217/Aβ1-42 ratio is the first blood-based assay cleared by the FDA to identify amyloid pathology, supporting clinical triage. Complementary biomarkers, including plasma Aβ42/40, glial fibrillary acidic protein, and neurofilament light chain, reflect amyloid burden, astroglial activation, and neurodegeneration. Clinical adoption remains limited by inter-assay variability, inconsistent diagnostic thresholds, and the lack of surrogate endpoints for treatment monitoring and adverse-event assessment.

CONCLUSIONS: Blood-based biomarkers are best incorporated into structured, stepwise diagnostic and therapeutic frameworks rather than replacing established reference standards. Progress will require assay harmonization, prospective validation, and interpretable biomarker-guided care pathways to support scalable, safe implementation of disease-modifying therapies in routine dementia care.},
}

@article {pmid42800673,
year = {2026},
author = {de Leve, SJ and Wang, X and Alavifard, H and Dara, L and DeLeve, LD},
title = {Reversing liver sinusoidal endothelial aging restores clearance of amyloid-beta and LDL.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {113608},
doi = {10.1016/j.jbc.2026.113608},
pmid = {42800673},
issn = {1083-351X},
abstract = {In healthy liver, large macromolecules pass freely into the space of Disse through liver sinusoidal endothelial cell (LSEC) fenestration. In aging, LSEC fenestration is largely lost (pseudocapillarization). We hypothesized that restoring aged LSECs' fenestration would enhance passage into the space of Disse of large-diameter (>50 nm) triglyceride-rich lipoproteins to which the majority of circulating amyloid-beta is bound and permit hepatocyte uptake of amyloid-beta: in aged rats, two weeks of the soluble guanylate cyclase activator cinaciguat restored fenestration; circulating amyloid-beta 40 levels halved, returning to levels found in young rats. Surprisingly, cinaciguat also reversed age-related increases in LDL (a smaller, 20-30 nm diameter lipoprotein), which crosses the sinusoidal endothelial barrier even when LSECs are defenestrated. We therefore investigated additional mechanisms by which LSECs promote hepatocyte clearance. Whereas primary hepatocytes had minimal uptake of amyloid-beta 40 or LDL, hepatocytes cultured in young rat LSEC conditioned medium retained their uptake function. Aged rat LSEC conditioned medium did not facilitate hepatocyte amyloid-beta 40 and LDL uptake but treating aged rats with cinaciguat restored aged rat LSECs paracrine signaling. We discovered that heparin-binding epidermal growth factor-like growth factor (HB-EGF) mediates this LSEC-hepatocyte interaction and that HB-EGF is synthesized but not secreted by aged rat LSECs; cinaciguat treatment restores aged LSECs' HB-EGF secretion. Treatment reversed age-associated loss of LDLR and LRP1 surface expression in rat hepatocytes. This study identifies a candidate therapy to address age-related increases in circulating amyloid-beta and LDL and elucidates an intercellular crosstalk mechanism that governs these phenomena.},
}

@article {pmid42801050,
year = {2026},
author = {Youn, BY and Park, S and Song, D and Nam, KC},
title = {Digital twin for neurological conditions: a systematic scoping review.},
journal = {Biomedical engineering letters},
volume = {16},
number = {5},
pages = {1219-1242},
pmid = {42801050},
issn = {2093-985X},
abstract = {Digital twin technology has emerged as a promising approach for advancing precision medicine in complex diseases, particularly in neurology. This scoping review aimed to systematically map the current literature on digital twin applications in neurological conditions, focusing on study characteristics, modeling approaches, data sources, and clinical applications. A comprehensive search across six databases from inception to February 2026 identified 36 studies that met the inclusion criteria. The findings demonstrated a rapid increase in publications since 2023, with Alzheimer's disease (n = 14) and stroke (n = 12) representing the most frequently studied conditions. Data-driven and machine learning-based models were the most common approaches, followed by mechanistic and hybrid models. Major application domains included clinical trial optimization, disease progression modeling, risk prediction, and personalized treatment. However, most studies were proof-of-concept or retrospective in design, with limited external validation and no randomized controlled trials identified. Additionally, many models lacked continuous real-time data integration, indicating that few met the criteria of fully dynamic digital twins. These findings suggest that while digital twins hold substantial potential to transform precision neurology, significant challenges remain in terms of methodological rigor, standardization, and clinical translation. Future research should prioritize prospective validation, integration of multimodal real-world data, and the development of standardized frameworks to support safe and effective implementation.},
}

@article {pmid42801166,
year = {2026},
author = {Wang, Y and Cai, J and Kong, X and Li, J and Ge, Y and Zhang, Y and Chen, Y and Zhu, M and Gong, H and Zhao, D and Pi, J},
title = {Promising Roles of Selenium Nanoparticles in Anti-Tuberculosis Therapy: Opportunities and Challenges.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {627381},
pmid = {42801166},
issn = {1178-2013},
mesh = {*Selenium/chemistry/pharmacology/administration & dosage ; Humans ; Animals ; *Tuberculosis/drug therapy ; *Antitubercular Agents/chemistry/pharmacology/administration & dosage ; *Nanoparticles/chemistry ; Mycobacterium tuberculosis/drug effects ; },
abstract = {Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the most threatening infectious disease worldwide. Selenium, an essential micronutrient, is incorporated into selenoproteins such as glutathione peroxidase, which modulate lipid peroxidation and immune responses, thus playing pivotal roles in host defense against infection and control of Mtb dissemination. As an emerging class of selenium-based medicines, selenium nanoparticles (SeNPs) have demonstrated attractive anti-tuberculosis potential based on their favorable bioactivity, lower toxicity compared, high drug-loading capacity, sustained-release kinetics, and enhanced targeting specificity. Beyond their anti-TB potential, SeNPs have shown significant promise in various biomedical applications, including the treatment of diabetes, liver disease, Alzheimer's disease, and cancer, owing to their ability to modulate oxidative stress, inflammation, and apoptotic pathways. This review explores the relationship between selenium and the occurrence and development of tuberculosis, evaluates the potential of serum selenium as an auxiliary diagnostic biomarker, and outlines common preparation methods for SeNPs, including physical, chemical, and biological synthesis approaches. Furthermore, this review systematically summarizes the anti-tuberculosis functions of SeNPs, detailing multiple mechanisms such as accelerating Mtb-lysosome fusion, modulating intracellular ROS levels, driving M1 macrophage polarization, and inhibiting the PI3K/AKT/mTOR signaling pathway to collectively trigger autophagy and apoptosis in Mtb-infected macrophages. These insights may support the development of new anti-tuberculosis technologies based on SeNPs. Furthermore, we also address the key challenges hindering the clinical translation of SeNPs: the long-term in vivo tissue accumulation patterns of SeNPs have not been fully elucidated, long-term systemic nanotoxicity data remain scarce, almost all anti-tuberculosis studies are restricted to in vitro cell experiments and animal models, and the translational pathway from laboratory studies to clinical practice remains ambiguous.},
}

*Selenium/chemistry/pharmacology/administration & dosage
Humans
Animals
*Tuberculosis/drug therapy
*Antitubercular Agents/chemistry/pharmacology/administration & dosage
*Nanoparticles/chemistry
Mycobacterium tuberculosis/drug effects

@article {pmid42801200,
year = {2026},
author = {Liu, R and Yue, H and Li, X and Sun, W and Yang, J},
title = {The Versatile Roles of Exosomes in Neurodegenerative Disorders: From Pathological Mechanism and Diagnostic Biomarkers to Therapeutic Application.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {631482},
pmid = {42801200},
issn = {1177-8881},
mesh = {Humans ; *Exosomes/metabolism/pathology ; *Neurodegenerative Diseases/diagnosis/drug therapy/metabolism/pathology/therapy ; Biomarkers/metabolism/analysis ; Animals ; },
abstract = {Neurodegenerative diseases are characterized by cognitive or motor impairments resulting from the progressive degeneration of neurons or myelin sheaths. Currently, the majority of these disorders remain incurable, leading to significant detriments in patients' quality of life and imposing substantial economic burdens. Exosomes are a type of extracellular vesicles secreted by cells into the extracellular space, typically range from 30 to 150 nanometers in diameter. These vesicles have been identified in a variety of cell types and can participate in various physiological and pathological processes, including intercellular transport of biomolecules, signal transduction, immune modulation, tissue repair, facilitation of tumor metastasis, and evasion of immune surveillance by cancer cells. In recent years, the potential applications of exosomes in neurodegenerative diseases have garnered increasing attention. Their roles encompass early diagnostic biomarker functions, vehicles for drug delivery and therapeutic agents, mediators in the propagation of pathogenic proteins, and regulators of neuroinflammatory responses. In this review, we try to aims to synthesize recent progress in exosome isolation techniques, elucidate the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), and examine the diagnostic and therapeutic applications of exosomes within these conditions. Furthermore, it addresses current limitations in exosome-based applications and explores potential strategies to overcome these challenges. The insights of this review may provide the research directions and guidance for future related researchers in these fields.},
}

Humans
*Exosomes/metabolism/pathology
*Neurodegenerative Diseases/diagnosis/drug therapy/metabolism/pathology/therapy
Biomarkers/metabolism/analysis
Animals

@article {pmid42796101,
year = {2026},
author = {Lee, J},
title = {Blood Amyloid-β Reduction Following Chongnoi-tang Treatment in Alzheimer's Spectrum Conditions: A Retrospective Pilot Observational Study.},
journal = {Journal of clinical medicine},
volume = {15},
number = {18},
pages = {},
pmid = {42796101},
issn = {2077-0383},
abstract = {BACKGROUND/OBJECTIVES: Anti-amyloid immunotherapies reduce amyloid-β (Aβ) plaques but carry a 15-35% risk of amyloid-related imaging abnormalities (ARIA), particularly in APOE ε4/ε4 carriers. This preliminary observational study evaluated blood Aβ oligomer changes following treatment with the multi-component herbal formula Chongnoi-tang (CNT) and contextualized these findings against natural disease trajectories in National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Initiative (ADNI) reference cohorts.

METHODS: This retrospective pilot cohort included 16 patients with Alzheimer's spectrum conditions treated with CNT. Blood Aβ oligomers were measured using the AlzOn Plus immunoassay. Primary analysis (n = 13) excluded cases with a ceiling-level baseline value, an intercurrent potentially confounding condition, or no true baseline measurement.

RESULTS: Mean blood Aβ oligomer levels decreased by 15.8% ± 13.4% at 6 months (median -20.6%; 95% CI -23.9% to -7.8%; Wilcoxon signed-rank test, p < 0.001; paired Cohen's dz = 1.07). At each participant's final available follow-up, all 13 primary-analysis patients had values below baseline. High-risk patients (n = 4) showed a mean 25.7% reduction. Baseline Aβ level and 6-month percent biomarker change exhibited an exploratory, non-significant inverse trend in the Pearson correlation (r = -0.489, p = 0.090) that was weaker and non-significant in the Spearman sensitivity analysis (ρ = -0.300, p = 0.320), consistent with regression to the mean and mathematical coupling as plausible contributors. Importantly, all four APOE ε4/ε4 homozygotes showed Aβ reductions without ARIA-like clinical events. Mini-Mental State Examination (MMSE) worsening occurred in 37.5% (3/8) of CNT-treated patients versus 42.9% (15/35) in propensity-matched NACC controls (p = 0.89); given the small sample, this comparison is inconclusive.

CONCLUSIONS: In this small, uncontrolled pilot study, CNT was associated with blood Aβ reductions, which should be interpreted as a statistical association rather than confirmed evidence of a treatment effect; no treatment discontinuations due to adverse effects were documented in this small cohort, including among APOE ε4/ε4 carriers. These hypothesis-generating findings warrant further confirmation in prospective randomized controlled trials.},
}

@article {pmid42796281,
year = {2026},
author = {Nguyen, LTH and Nguyen, MT and Nguyen, TU},
title = {Computational Repurposing of Janus Kinase Inhibitors as Potential Therapeutic Candidates for Alzheimer's Disease.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {9},
pages = {},
pmid = {42796281},
issn = {1648-9144},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Janus Kinase Inhibitors/therapeutic use/pharmacology ; *Drug Repositioning/methods ; Molecular Docking Simulation/methods ; Computational Biology/methods ; Signal Transduction/drug effects ; },
abstract = {Background and Objectives: Alzheimer's disease (AD) is the most common neurodegenerative disorder, and current therapies provide only limited symptomatic relief without effectively slowing its progression. Increasing evidence suggests that aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling cascade contributes to AD-associated neuroinflammation. This study investigated the therapeutic potential and molecular mechanisms of JAK inhibitors in AD using integrated bioinformatics and network pharmacology approaches. Materials and Methods: Potential anti-AD targets of JAK inhibitors were identified using the SwissTargetPrediction and GeneCards databases. Functional enrichment, protein-protein interaction (PPI) analysis, transcriptomic validation using public datasets, regulatory network construction, molecular docking, normal mode analysis (NMA), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction were performed to investigate the potential mechanisms of action of these drugs in AD. Results: Our analysis identified 163 shared targets between JAK inhibitors and AD. Enrichment analysis revealed that these genes were primarily involved in protein phosphorylation and were enriched in key signaling pathways, including the neurotrophin, phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and mitogen-activated protein kinase (MAPK) signaling pathways. PPI analysis identified AKT1, BCL2, SRC, STAT3, and TNF as five highly ranked hub targets across multiple topological algorithms. Transcriptomic validation confirmed significantly higher expression of these targets in the prefrontal cortex of individuals with AD compared with normal subjects. Molecular docking indicated that pacritinib and momelotinib showed relatively favorable predicted interactions with the hub proteins, while NMA revealed differences in the predicted flexibility of the docked complexes. Furthermore, ADMET prediction showed that pacritinib possesses favorable pharmacokinetic properties for the treatment of AD. Conclusions: Collectively, these findings provide mechanistic insights into the potential effects of JAK inhibitors in AD and identify pacritinib as a computationally prioritized candidate that warrants experimental validation in appropriate AD models. However, as this study is based solely on computational analyses without wet-lab validation, the findings should be considered hypothesis-generating in silico evidence, and the potential safety concerns of pacritinib require further investigation.},
}

*Alzheimer Disease/drug therapy
Humans
*Janus Kinase Inhibitors/therapeutic use/pharmacology
*Drug Repositioning/methods
Molecular Docking Simulation/methods
Computational Biology/methods
Signal Transduction/drug effects

@article {pmid42796440,
year = {2026},
author = {Wang, LY and Yeh, SL and Hsu, ST and Huang, SM and Chau, CF and Chuang, CH},
title = {Erinacine C Attenuates Alzheimer's-like Pathology: A Study in APP/PS1 Mice and PC12 Cells.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {18},
pages = {},
pmid = {42796440},
issn = {1420-3049},
support = {109-2637-B-241-004-//National Science and Technology Council/ ; 110-2637-B-241-007-//National Science and Technology Council/ ; },
mesh = {Animals ; PC12 Cells ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics ; Rats ; Mice ; *Neuroprotective Agents/pharmacology/chemistry ; *Presenilin-1/genetics/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Apoptosis/drug effects ; *Amyloid beta-Protein Precursor/genetics/metabolism ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; Hippocampus/metabolism/drug effects/pathology ; Hericium/chemistry ; Proto-Oncogene Proteins c-akt/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition and cognitive decline. Clinical evidence indicates that Hericium erinaceus whole fruiting body powder offers limited therapeutic efficacy, which is suggested to be constrained by whole-food matrix interference and uncertainties in central nervous system (CNS) exposure. Therefore, we hypothesized that erinacine C (EC)-a purified active component from Hericium erinaceus mycelia-could resolve these limitations and potentially exhibit favorable neuroprotective effects owing to its low molecular weight and lipophilicity. In this study, we investigated the neuroprotective potential and associated signaling alterations of EC using APP/PS1 transgenic mice and Aβ25-35-induced PC12 cells. In vivo, oral administration of EC alleviated deficits in activities of daily living, as evidenced by improvements in nesting and burrowing behaviors, along with enhanced short-term spatial memory in the Y-maze test. EC treatment was associated with a reduction in hippocampal Aβ plaque accumulation, suppression of glial activation (GFAP and IBA1), and decreased IL-6 levels in both serum and hippocampal tissues. In vitro, EC intervention counteracted Aβ25-35-induced cytotoxicity in PC12 cells. Analysis of signaling markers revealed that EC treatment was accompanied by a restoration of p-Akt/Akt levels and a suppression of p-GSK3β (Tyr216) activation. Consequently, EC treatment was correlated with reduced tau hyperphosphorylation, the up-regulation of the anti-apoptotic protein Bcl-2, and the down-regulation of pro-apoptotic markers including Bax and cleaved-caspase-3, thereby lowering the total apoptotic rate. Taken together, these findings suggest that EC may mitigate cognitive impairment and neurodegeneration in parallel with alterations in the Akt/GSK3β/tau/caspase-3 signaling response, thereby representing a potentially promising therapeutic candidate for the intervention of AD.},
}

Animals
PC12 Cells
*Alzheimer Disease/drug therapy/pathology/metabolism/genetics
Rats
Mice
*Neuroprotective Agents/pharmacology/chemistry
*Presenilin-1/genetics/metabolism
Mice, Transgenic
Disease Models, Animal
Apoptosis/drug effects
*Amyloid beta-Protein Precursor/genetics/metabolism
Signal Transduction/drug effects
Amyloid beta-Peptides/metabolism
Hippocampus/metabolism/drug effects/pathology
Hericium/chemistry
Proto-Oncogene Proteins c-akt/metabolism

@article {pmid42796561,
year = {2026},
author = {Sharma, N and An, SSA},
title = {Small-Molecule NANT Therapeutics Targeting the Brain-Immune Axis in Alzheimer's Disease: Mechanisms, Clinical Progress, and Translational Challenges.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {18},
pages = {},
pmid = {42796561},
issn = {1420-3049},
support = {RS-2021-NR060117//National Research Foundation of Korea/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology Promotion/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/immunology/metabolism ; Animals ; *Brain/drug effects/immunology/metabolism ; Neuroinflammatory Diseases/drug therapy ; *Small Molecule Libraries/therapeutic use/pharmacology ; },
abstract = {Alzheimer's disease (AD) is now widely accepted as a complex disorder involving multiple interconnected pathological processes. Increasing evidence suggest that neuroinflammation and immune system dysregulation actively contribute to neurodegeneration, extending beyond the traditional view that the disease is driven solely by amyloid-β (Aβ) and tau pathology. With the advent of studies showing anti-amyloid antibodies to have only modest effects with significant toxicity, there has been a growing interest in investigating non-amyloid non-tau (NANT) treatment approaches. This review provided a general review of small molecules for neuroinflammation-based NANT therapies in AD. We reviewed several agents that affect the brain/immune axis, namely, kinase inhibitors (nelflamaimod and masitinib), NLRP3 inflammasome inhibitors (MCC950, selnoflast, and dapansutrile), TREM2 activators (VG-3927), gingipain inhibitors, PPARγ activators, KCa3.1 inhibitors, and repurposed drugs such as ambroxol and cromolyn. Some common drawbacks were identified for the drugs that failed to provide their anticipated effects. It was found that they all suffered from late-stage treatment, patient heterogeneity, inadequate central nervous system penetration, and poorly designed preclinical studies. Additional translational challenges included sex-specific differences in neuroimmune responses, APOE ε4-associated immune dysfunction, and the need for biomarker-guided patient selection. Although immune-targeted therapies remain strongly supported by biological evidence in AD, meaningful clinical progress will likely require earlier intervention strategies guided by biomarkers and therapies capable of targeting multiple disease pathways simultaneously.},
}

Humans
*Alzheimer Disease/drug therapy/immunology/metabolism
Animals
*Brain/drug effects/immunology/metabolism
Neuroinflammatory Diseases/drug therapy
*Small Molecule Libraries/therapeutic use/pharmacology

@article {pmid42797041,
year = {2026},
author = {Hailati, S and Yasheng, Y and Yin, Y and Jiang, C and Liu, Y and Ding, W and Dilimulati, D and Baishan, A and Paerhati, Y and Aikebaier, A and Dolkun, A and Zhou, W},
title = {Multi-Component Xinjiang Basil Essential Oil Mitigates Alzheimer's Disease-like Pathology Through Amyloid and Neuroinflammatory Modulation.},
journal = {Nutrients},
volume = {18},
number = {18},
pages = {},
pmid = {42797041},
issn = {2072-6643},
support = {2025D01E32//Natural Science Foundation for Distinguished Young Scholars of Xinjiang Uygur Autonomous Region/ ; 2025D01C329//Natural Science Foundation for Young Scholars of Xinjiang Uygur Autonomous Region/ ; 2022TSYCCX0035//Tianshan Talents-Youth Science and Technology Innovation Talents Training Program of Xinjiang Uygur Autonomous Region/ ; XJDX1713//Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology/ ; 2023//Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices/ ; 2023//Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Oils, Volatile/pharmacology/isolation & purification ; Mice ; *Neuroprotective Agents/pharmacology ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Ocimum basilicum/chemistry ; Male ; Mice, Transgenic ; Brain/metabolism/drug effects ; *Neuroinflammatory Diseases/drug therapy ; NF-kappa B/metabolism ; *Plant Oils/pharmacology ; Signal Transduction/drug effects ; NF-KappaB Inhibitor alpha/metabolism ; },
abstract = {Background: Basil (Ocimum basilicum L.) is a herbaceous plant belonging to the family Lamiaceae. It is not only edible, but it also has nutritional value and can be used for medicinal purposes. Previous studies suggest that basil-derived extracts may protect neurons from injury. Objectives: Our research aimed to investigate whether basil essential oil (BEO) from Xinjiang has a neuroprotective effect in Alzheimer's disease (AD)-like pathological mouse model and to elucidate the mechanism underlying this effect. Methods: The essential oil was extracted using steam distillation. UHPLC-MS/MS technology was used to identify constituents detected in brain tissue following intranasal administration. In the experiment, BEO was administered intranasally to APP/PS1 mice for 4 weeks, and its therapeutic effects on AD-like pathological features were evaluated through behavioral and biochemical assessments. Results: The results showed that there were 787 compounds in the BEO, of which 30 putatively annotated compounds were detected in brain tissue after intranasal administration. Most of these were prenol lipids (36%). BEO markedly enhanced spatial learning and cognitive abilities in APP/PS1 mice, while also reducing neurodegeneration within the hippocampus and decreasing Aβ1-40 and Aβ1-42 levels. BEO additionally lowered the levels of IL-1β, IL-6, and TNF-α and inhibited the activation of astrocytes and microglia. BEO exerted its neuroprotective effects by reducing the activation of the IκB-α/NF-κB pathway. Conclusions: BEO exerted neuroprotective-like effects in this AD mouse model accompanied by anti-inflammatory activity and suppression of amyloid-β (Aβ) accumulation, and BEO treatment was associated with reduced IκB-α/NF-κB pathway activation. This research demonstrated that BEO might serve as a natural treatment against AD.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
*Oils, Volatile/pharmacology/isolation & purification
Mice
*Neuroprotective Agents/pharmacology
*Amyloid beta-Peptides/metabolism
Disease Models, Animal
*Ocimum basilicum/chemistry
Male
Mice, Transgenic
Brain/metabolism/drug effects
*Neuroinflammatory Diseases/drug therapy
NF-kappa B/metabolism
*Plant Oils/pharmacology
Signal Transduction/drug effects
NF-KappaB Inhibitor alpha/metabolism

@article {pmid42797331,
year = {2026},
author = {Zeng, W and Zhou, D and Wang, T and Ma-Högemeier, ZL and Cai, S and Liu, B and Song, C and Guo, L and Zhai, R and Song, X and He, Z and Dong, Y},
title = {Manganese Dioxide Nanoparticles Protect PC12 Cells Against H2O2-Induced Oxidative Stress Injury by Regulating PI3K/Akt-Mediated Autophagy.},
journal = {Pharmaceutics},
volume = {18},
number = {9},
pages = {},
pmid = {42797331},
issn = {1999-4923},
support = {JCYJ20240813113330039//Shenzhen Science and Technology Innovation Commission/ ; 2023KTSCX126//Natural Science Foundation of Education Department of Guangdong Province/ ; 202305AF150139//Natural Science Foundation of Yunnan Province Science and Technology Department/ ; YSZJGZZ-2021083//Natural Science Foundation of Yunnan Province Science and Technology Department/ ; },
abstract = {Background: Oxidative stress-mediated neuronal injury is critically involved in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Manganese dioxide (MnO2), owing to its intrinsic reactive oxygen species (ROS)-scavenging capacity, has emerged as a promising neuroprotective candidate; however, the underlying molecular mechanisms remain insufficiently defined. Methods: Bovine serum albumin-templated MnO2 nanoparticles (BSA-MnO2 NPs) were synthesized, and their protective effects were evaluated in H2O2-treated PC12 cells. Results: BSA-MnO2 NPs significantly inhibited H2O2-induced reductions in cell viability, ROS overproduction, and mitochondrial membrane potential disruption. Mechanistically, H2O2 increased both LC3-II and p62 levels, indicating impaired autophagic flux. Activation of autophagy by serum starvation alleviated H2O2-induced injury, whereas chloroquine exacerbated cellular damage and abolished the protective effects of BSA-MnO2 NPs, suggesting that the restoration of autophagy contributes to BSA-MnO2 NPs-mediated neuroprotection. Further analysis showed that BSA-MnO2 NPs enhanced Akt phosphorylation, while LY294002, a PI3K inhibitor, suppressed Akt activation, disrupted autophagy regulation, and eliminated their neuroprotective effects. In contrast, chloroquine did not affect Akt phosphorylation, indicating that PI3K/Akt signaling acts upstream of autophagy regulation. Conclusions: Collectively, these findings demonstrate that BSA-MnO2 NPs protect PC12 cells against H2O2-induced oxidative injury by restoring autophagy through the PI3K/Akt signaling pathway, highlighting a potential role of BSA-MnO2 NPs in the treatment of oxidative-stress-related neurodegenerative disorders.},
}

@article {pmid42797432,
year = {2026},
author = {Zhou, Y and Liu, B and Wang, H and Cao, L},
title = {Two-Dimensional MXene-Loaded Butylphthalide Enhances the Treatment of Alzheimer's Disease by Inhibiting Ferroptosis and Oxidative Stress.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {9},
pages = {},
pmid = {42797432},
issn = {1424-8247},
support = {23XD1402500//Shanghai Outstanding Academic Leaders/ ; },
abstract = {Introduction: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder involving ROS and ferroptosis. MXene, a 2D material, functions as both a drug carrier and ROS scavenger. Butylphthalide (NBP), a neuroprotective agent, suffers from poor aqueous solubility and bioavailability. This study synthesized Ti2C@BSA-NBP, a novel MXene nanocomposite, to enhance NBP delivery and therapeutic efficacy for AD. Materials and Methods: Ti2C@BSA-NBP was synthesized via self-assembly and amidation reaction, and characterized by multiple techniques. In vitro, ROS-scavenging capacity, mitochondrial function, and ferroptosis markers were assessed in H2O2-injured cells. In vivo efficacy was evaluated in an AD mouse model via behavioral, histopathological, and biochemical analyses. Results: The nanocomposite exhibited robust ROS-scavenging activity in vitro, significantly attenuating ROS, restoring mitochondrial function, and reversing ferroptosis markers. In vivo, Ti2C@BSA-NBP ameliorated learning/memory deficits, partially repaired neuronal morphology, and suppressed neuroinflammation. Mechanistically, it downregulated ACSL4 and Aβ overexpression while restoring GPX4 inhibition. Discussion: Ti2C@BSA-NBP exerts synergistic neuroprotection through MXene-mediated ROS clearance and NBP-mediated multi-target regulation, counteracting oxidative stress, ferroptosis, and neuroinflammation. Conclusions: Ti2C@BSA-NBP is a promising multifunctional nanoplatform integrating antioxidant activity, enhanced drug delivery, and ferroptosis modulation for AD therapy.},
}

@article {pmid42794721,
year = {2026},
author = {Velázquez De Castro-Bono, A and Castro-Luna, G and Guil-Guerrero, JL},
title = {Reframing Alzheimer's Disease Through a Redox-Metabolic Framework.},
journal = {International journal of molecular sciences},
volume = {27},
number = {18},
pages = {},
pmid = {42794721},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; Oxidation-Reduction ; Animals ; Mitochondria/metabolism ; Oxidative Stress ; Amyloid beta-Peptides/metabolism ; Glucose/metabolism ; Signal Transduction ; Brain/metabolism/pathology ; Energy Metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) has been conceptualised as a proteinopathy driven by amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles. AD should not be understood as exclusively a proteinopathy or a metabolic/redox disorder, but as a network of interacting processes in which metabolic dysfunction, mitochondrial impairment, redox dysregulation, amyloid-β, tau, neuroinflammation, metal dyshomeostasis, and regulated cell death reinforce one another. This review examines AD through a redox-metabolic framework integrating cerebral glucose metabolism, insulin signalling, mitochondrial bioenergetics, metal homeostasis, and regulated cell death. We discuss how glucose hypometabolism, impaired oxidative phosphorylation, and weakened antioxidant defences may promote reactive oxygen species production and self-reinforcing oxidative and metabolic dysfunction. We examine interactions with amyloid-β and tau pathology, glial immunometabolism, gut-brain signalling, neuroinflammation, and metal-mediated toxicity. Advances in multi-omics, blood-based metabolomic and lipidomic biomarkers, and imaging may enable earlier biological stratification. Therapeutic strategies targeting mitochondria, NRF2 signalling, metabolic dysfunction, metal dyshomeostasis, and regulated oxidative cell death are evaluated based on current evidence and their potential complementarity with amyloid-directed therapies. Although temporal relationships remain unresolved, redox-metabolic dysfunction may represent an early determinant and amplifier of neuronal vulnerability. Evidence for lecanemab and donanemab supports an integrative rather than replacement model of AD treatment. This framework may facilitate earlier diagnosis, patient stratification, and complementary disease-modifying interventions.},
}

Humans
*Alzheimer Disease/metabolism/pathology
Oxidation-Reduction
Animals
Mitochondria/metabolism
Oxidative Stress
Amyloid beta-Peptides/metabolism
Glucose/metabolism
Signal Transduction
Brain/metabolism/pathology
Energy Metabolism
tau Proteins/metabolism